GATA and PIF transcription factors regulate light-induced ...€¦ · significantly induce the indole and iridoid pa. thway genes, resulting in increased accumulation of . 92. strictosidine,

1

Short title: 1

CrPIF1–CrGATA1 regulate vindoline biosynthesis 2

3

Corresponding authors: Ling Yuan and Sitakanta Pattanaik, Department of Plant and Soil 4

Sciences and Kentucky Tobacco Research and Development Center, University of Kentucky, 5

Lexington, KY, USA. 6

Email: [email protected] and [email protected] 7

Phone: 859-257-4806; 859-257-1976 8

Fax: 859-323-1077 9

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GATA and PIF transcription factors regulate light-induced vindoline biosynthesis in 11

Catharanthus roseus 12

13

Yongliang Liu1,2 #, Barunava Patra2, #, Sitakanta Pattanaik2, Ying Wang1 and Ling Yuan1, 2 14

15

1Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic 16

Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, PR 17

China 18

2Department of Plant and Soil Sciences and Kentucky Tobacco Research and Development 19

Center, University of Kentucky, Lexington, KY, USA 20

# These authors have contributed equally to this work. 21

One sentence summary: 22

A regulatory module consisting of Phytochrome Interacting Factor (PIF) and GATA transcription 23

factors regulates light-induced vindoline biosynthesis in Catharanthus roseus seedlings. 24

Author contribution: 25

L.Y., B.P., S.P. and Y.W. designed the research; Y.L., B.P., and S.P. performed experiments; Y.L. 26

and B.P. analyzed data; and Y.L., B.P. S.P., Y.W. and L.Y. wrote the manuscript. 27

28

Funding information: 29

This work is supported partially by the Harold R. Burton Endowed Professorship to L.Y. and by 30

the National Science Foundation under Cooperative Agreement no. 1355438 to L.Y. 31

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Plant Physiology Preview. Published on May 13, 2019, as DOI:10.1104/pp.19.00489

Copyright 2019 by the American Society of Plant Biologists

Plant Physiology Preview. Published on May 13, 2019, as DOI:10.1104/pp.19.00489

Copyright 2019 by the American Society of Plant Biologists

www.plantphysiol.orgon June 24, 2020 - Published by Downloaded from Copyright © 2019 American Society of Plant Biologists. All rights reserved.

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2

ABSTRACT 33

Catharanthus roseus is the exclusive source of an array of terpenoid indole alkaloids including 34

the anticancer drugs vincristine and vinblastine, derived from the coupling of catharanthine and 35

vindoline. Leaf-synthesized vindoline is regulated by light. A seven-step enzymatic process is 36

involved in the sequential conversion of tabersonine to vindoline; however, the regulatory 37

mechanism controlling expression of genes encoding these enzymes has not been elucidated. 38

Here, we identified CrGATA1, an LLM-domain GATA transcription factor that regulates light-39

induced vindoline biosynthesis in C. roseus seedlings. Expression of CrGATA1 and the vindoline 40

pathway genes T16H2, T3O, T3R, D4H, and DAT was significantly induced by light. In addition, 41

CrGATA1 activated the promoters of five light-responsive vindoline pathway genes in plant 42

cells. Two GATC-motifs in the D4H promoter were critical for CrGATA1-mediated 43

transactivation. Transient overexpression of CrGATA1 in C. roseus seedlings resulted in 44

upregulation of vindoline pathway genes and increased vindoline accumulation. Conversely, 45

virus-induced gene silencing (VIGS) of CrGATA1 in young C. roseus leaves significantly 46

repressed key vindoline pathway genes and reduced vindoline accumulation. Furthermore, we 47

showed that a C. roseus Phytochrome Interacting Factor, CrPIF1, is a repressor of CrGATA1 and 48

vindoline biosynthesis. Transient overexpression or VIGS of CrPIF1 in C. roseus seedlings 49

altered CrGATA1 and vindoline pathway gene expression in the dark. CrPIF1 repressed 50

CrGATA1 and DAT promoter activity by binding to G/E-box/PBE elements. Our findings reveal 51

a regulatory module involving PIF–GATA that governs light-mediated biosynthesis of 52

specialized metabolites. 53

54

Key words: GATA transcription factor, phytochrome interacting factor (PIF), vindoline 55

biosynthesis, transcriptional regulation, Catharanthus roseus. 56

57



3

INTRODUCTION 58

Catharanthus roseus (Madagascar periwinkle) is the unique source of more than hundred of 59

terpenoid indole alkaloids (TIAs) including the two anticancer drugs, vincristine and vinblastine. 60

Biosynthesis of TIAs (Supplemental Fig. S1) starts with the production of strictosidine, which is 61

formed by the condensation of the terpenoid precursor secologanin and the indole precursor 62

tryptamine (Courdavault et al., 2014; Pan et al., 2016; Thamm et al., 2016). Strictosidine serves 63

as a universal precursor for various TIAs, including ajmalicine, serpentine, catharanthine, and 64

tabersonine. Tabersonine is sequentially converted to vindoline by a seven-step enzymatic 65

process, and genes encoding the seven enzymes have been characterized (Vazquez-Flota et al., 66

1997; St-Pierre et al., 1998; Levac et al., 2008; Liscombe et al., 2010; Besseau et al., 2013; Qu et 67

al., 2015). Vincristine and vinblastine are derived from coupling of vindoline and catharanthine. 68

Expression of TIA biosynthetic pathway genes in four different cell types is elicited by 69

environmental cues and phytohormones (Courdavault et al., 2014). 70

71

In C. roseus, a number of transcription factors (TFs) regulate TIA biosynthesis. These TFs 72

include the Apetala2/Ethylene Response Factors (AP2/ERFs) ORCA2/3/4/5 and CR1 (Menke et 73

al., 1999; van der Fits and Memelink, 2000; Pan et al., 2012; Li et al., 2013; Liu et al., 2017; 74

Paul et al., 2017), basic helix-loop-helix (bHLH) TFs CrMYC2, BIS1/2, and RMT1 (Zhang et al., 75

2011; Van Moerkercke et al., 2015; Van Moerkercke et al., 2016; Patra et al., 2018), Cys2/His2-76

type zinc finger proteins ZCT1/2/3 (Pauw et al., 2004), MYB-like factor CrBPF1 (van der Fits et 77

al., 2000; Li et al., 2015), G-box binding factors CrGBF1/2 (Sibéril et al., 2001; Sui et al., 2018), 78

WRKY TF CrWRKY1 (Suttipanta et al., 2011), and the jasmonate ZIM-domain (JAZ) proteins 79

(Patra et al., 2018). ORCA3, ORCA4 and ORCA5, which form a physical cluster, regulate a 80

number of genes in the TIA pathway through overlapping yet distinct mechanisms (van der Fits 81

and Memelink, 2000; Paul et al., 2017). CrMYC2 activates ORCA3 by binding to a qualitative 82

sequence in the promoter (Zhang et al., 2011), whereas it indirectly activates ORCA4 and 83

ORCA5 (Paul et al., 2017). In addition, CrMYC2 interacts with CrGBF1 and CrGBF2 to 84

modulate TIA biosynthesis (Sui et al., 2018). The CrMYC2–ORCA cascade has limited effects 85

on expression of genes in the iridoid branch of TIA pathway. However, a recent study has 86

demonstrated that transient overexpression of a de-repressed CrMYC2 (CrMYC2D126N

) in C. 87

roseus flower petals significantly activates expression of iridoid pathway genes (Schweizer et al., 88



4

2018). BIS1 and BIS2 are major regulators of the iridoid pathway (Van Moerkercke et al., 2015; 89

Van Moerkercke et al., 2016). Transient overexpression of CrMYC2D126N

, BIS1, and ORCA3 90

significantly induce the indole and iridoid pathway genes, resulting in increased accumulation of 91

strictosidine, 16-hydroxytabersonine, and horhammericine (Schweizer et al., 2018). The bHLH 92

TF RMT1 and JAZ proteins mediate crosstalk between iridoid and terpenoid pathways to 93

balance TIA accumulation (Patra et al., 2018). However, our knowledge is limited on regulation 94

of genes involved in the sequential conversion of tabersonine to vindoline in C. roseus leaves. 95

Combinatorial overexpression of wild-type or de-repressed CrMYC2 (CrMYC2D126N

), along with 96

BIS1 and/or ORCA3 does not induce the expression of vindoline pathway genes (Schweizer et al., 97

2018), suggesting that other TFs are likely involved in regulation of the vindoline pathway. 98

99

In C. roseus, while tabersonine is produced in leaves and roots, vindoline production is leaf-100

specific and light dependent (De Luca et al., 1986). In addition, previous studies suggest that the 101

conversion of tabersonine to vindoline is phytochrome dependent (Aerts and De Luca, 1992). 102

Light regulates a myriad of physiological and developmental processes in plants, including 103

photoperiodism, photomorphogenesis, seed germination and shade-avoidance (Jiao et al., 2007). 104

Light also plays crucial roles in biosynthesis of specialized metabolites. The TFs in bHLH, basic 105

leucine zipper (bZIP), and GATA families are known to control light-responsive gene expression 106

in plants (Richter et al., 2010; Toledo-Ortiz et al., 2014; Klermund et al., 2016). GATA TFs, 107

widely distributed in eukaryotes, are characterized by the class IV zinc finger motif (CX2CX17-108

20CX2C) (Lowry and Atchley, 2000). In Arabidopsis and rice (Oryza sativa), GATA TFs are 109

divided into four conserved and distinct classes, A through D (Reyes et al., 2004). Class B 110

GATAs (B-GATAs) are further sub-divided into two families based on the presence of conserved 111

LLM (Leucine-Leucine-Methionine) domain or HAN (HANABA TARANU) domain (Behringer 112

and Schwechheimer, 2015). In Arabidopsis, expression of two homologous LLM B-GATAs, 113

GNC (GATA-nitrate-inducible-carbon metabolism-involved) and GNL (GNC-like/cytokinin-114

responsive GATA factor 1), is induced by light known to regulate chlorophyll biosynthesis, 115

chloroplast development, nitrate metabolism, seed germination, flowering time, hypocotyl 116

elongation, and stomata development (Richter et al., 2010; Hudson et al., 2013; Richter et al., 117

2013a; Richter et al., 2013b; Klermund et al., 2016; Ranftl et al., 2016; Xu et al., 2017; Bastakis 118

et al., 2018). In addition to GATA TFs, a small group of bHLH TFs, the Phytochrome Interacting 119



5

Factors (PIFs) play crucial role in light-responsive gene expression and downstream biological 120

processes through interacting with phytochromes in plants (Leivar and Monte, 2014). 121

Phytochromes are the receptor of red and far-red light signals and exist in either the inactive Pr 122

form or the active Pfr form (Pham et al., 2018). PIFs physically interact with the active Pfr, 123

leading to degradation by the 26S/ubiquitin proteasome system (26S/UPS). The PIF degradation 124

triggers massive transcriptional reprogramming that regulates various biological processes 125

(Leivar and Monte, 2014; Paik et al., 2017). Light-mediated anthocyanin accumulation in 126

Arabidopsis is regulated by PIFs (Shin et al. 2007; Liu et al. 2015). In Arabidopsis, GNC and 127

GNL are direct targets of PIFs in the regulation of seed germination, flowering time, hypocotyl 128

elongation, and stomata development (Richter et al., 2010; Klermund et al., 2016; Ranftl et al., 129

2016). In fungi, GATA-type TF Csm1 has been reported to regulate biosynthesis of the red 130

pigments bikaverin and fusarubins in Fusarium fujikuroi (Niehaus et al., 2017); it is unclear, 131

however, whether GATA TFs are involved in the regulation of specialized metabolite 132

biosynthesis in plants. 133

134

The light and phytochrome dependent nature of vindoline biosynthesis led us to hypothesize that 135

a light-associated transcriptional cascade is involved in the conversion of tabersonine to 136

vindoline in C. roseus seedlings. In this study, we characterized a light-induced C. roseus LLM 137

domain B-GATA, termed CrGATA1, which predominantly expresses in the leaf. CrGATA1 138

activates the promoters of key vindoline biosynthetic genes in plant cells. In addition, transient 139

overexpression or virus-induced gene silencing (VIGS) of CrGATA1 in C. roseus seedlings 140

significantly altered vindoline pathway gene expression and vindoline accumulation. We also 141

demonstrated that a C. roseus PIF (CrPIF1) acts as an upstream negative regulator of CrGATA1, 142

resulting in repression of vindoline biosynthetic genes in the dark. De-repression of CrGATA1, 143

presumably through degradation of CrPIF1 under light, leads to increased accumulation of 144

vindoline. Our findings reveal a previously uncharacterized regulatory module in C. roseus 145

involving PIF-GATA that governs light-induced vindoline biosynthesis in seedlings. 146

147

Results 148

Vindoline pathway is induced by light in C. roseus seedlings 149

Conversion of tabersonine to vindoline is responsive to developmental as well as environmental 150



6

cues, such as light, in C. roseus seedlings (De Luca et al., 1986). Of the seven genes involved in 151

the conversion, expression of deacetylvindoline-4-O-acetyltransferase (DAT) and 152

desacetoxyvindoline-4-hydroxylase (D4H) is induced by light (Vazquez-Flota et al., 1997; St-153

Pierre et al., 1998; Vazquez-Flota and De Luca, 1998). To determine the light-responsive 154

expression of tabersonine–vindoline conversion genes and alkaloid accumulation, seven-day-old 155

etiolated C. roseus seedlings were exposed to continuous white light for 1h, 4h, 10h, 24h, 48h, 156

and 96h, and the aerial parts of the seedlings were collected for gene expression and alkaloids 157

analysis. Expression of tabersonine-16-hydroxylase 2 (T16H2), tabersonine-3-oxygenase (T3O), 158

D4H, and DAT showed gradual increase upon exposure to light that peaked at 24h. Expression 159

of tabersonine-3-reductase (T3R) was highest at 48h of light treatment and declined thereafter 160

(Fig. 1A). However, expression of 16-hydroxytabersonine-O-methyltransferase (16OMT) and 3-161

hydroxy-16-methoxy-2,3-dihydrotabersonine N-methyltransferase (NMT) did not significantly 162

change in response to light (Fig. 1A), which corroborates with earlier studies showing the 163

activities of 16OMT and NMT were less sensitive to light (St-Pierre and De Luca, 1995; Levac 164

et al., 2008). We also measured the expression of two upstream TIA pathway genes 165

(Supplemental Fig. S1), tryptophan decarbxylase (TDC) and strictosidine synthase (STR), in 166

dark- and light-treated seedlings. In contrast to the rapid light induction for the vindoline 167

pathway genes (within 4 h), expression of TDC and STR did not significantly change by light-168

treatment up to 24 h (Supplemental Fig. S2A). In addition, we compared catharanthine, 169

tabersonine, and vindoline in etiolated and light-treated C. roseus seedlings. We did not observe 170

significant differences in catharanthine accumulation between dark- and light-treated seedlings 171

(Supplemental Fig. S2B). However, we detected a significant increase of vindoline and a 172

decrease of tabersonine in seedlings exposed to light for 24 and 96 h (Fig. 1B). We also 173

compared levels of catharanthine, tabersonine, and vindoline in normal, 11-day-old C. roseus 174

seedlings grown under continuous light to those of dark-grown seedlings exposed to light. We 175

found that vindoline levels were significantly higher in light grown seedlings (Supplemental Fig. 176

S2C) compared to the etiolated ones exposed to light for 24 and 96 h (Fig. 1B). Taken together, 177

the results suggest that expression of five of the seven vindoline pathway genes and vindoline 178

accumulation in C. roseus seedlings are light-inducible. 179

180

181



7

Putative light-responsive cis-elements are present in the promoters of light-inducible 182

vindoline pathway genes 183

The light-inducible expression of the five vindoline pathway genes prompted us to analyze their 184

promoters for presence of putative light-responsive cis-elements. We therefore retrieved the 185

promoter sequences (2kb upstream of the first ATG of coding frame) of the five light-responsive 186

genes, T16H2, T3O, T3R, D4H, and DAT, from the Medicinal Plant Genomics Resource (MPGR; 187

http://medicinalplantgenomics.msu.edu/) and scanned the promoter sequences using PlantCARE 188

(Lescot et al., 2002). We identified multiple known light responsive cis-elements, of which the 189

GATA, Box 4, and Box I motifs are present in the promoters of all five light-responsive 190

vindoline pathway genes (Supplemental Table S1). GATA and GATC cis-elements were also 191

found in the promoters of two upstream vindoline pathway genes, TDC and STR, although their 192

expression were not significantly induced by light. The GATA-motif, consisting of W-G-A-T-A-193

R sequence (in which W denotes A or T, and R denotes A or G), and the GATC-motif are 194

binding sites for light-inducible GATA TFs (Lowry and Atchley, 2000; Newton et al., 2001; 195

Sugimoto et al., 2003; Manfield et al., 2007). Although the Box 4 and Box I elements have been 196

identified to be present in many promoters of light-inducible genes, the TFs targeting these 197

elements are unclear. Therefore, we focused on GATA family TFs of C. roseus for their potential 198

roles in regulating light-inducible vindoline biosynthesis. 199

200

CrGATA1 is light-inducible and co-expressed with vindoline pathway genes 201

We identified 24 putative GATA TFs in C. roseus genome. We next used C. roseus 202

transcriptomic resources (Góngora-Castillo et al., 2012) (Accession no. SRA030483) to perform 203

co-expression analysis of GATA TFs and genes involved in vindoline biosynthesis. Hierarchical 204

cluster analysis of the putative GATA TFs and the five light-inducible vindoline pathway genes 205

reveled that two GATA TFs (CRO_T134526 and CRO_T117711) are tightly co-expressed with 206

the vindoline pathway genes (Supplemental Fig. S3). Quantitative RT-PCR (RT-qPCR) was 207

performed to measure the expression of two GATA TFs and vindoline pathway genes in arial 208

parts and roots of C. roseus seedlings. As shown in Figure 2A, the vindoline pathway genes, as 209

well as CRO_T134526 and CRO_T117711, are preferentially expressed in aerial parts of the 210

seedlings (Fig. 2A). Expression of CRO_T134526 and CRO_T117711 were also measured in C. 211

roseus seedlings exposed to light for 1h, 4h, 10h, 24h, 48h, and 96h. Under light-treatment, only 212



8

CRO_T134526 expression was induced (Fig. 2B) and peaked at 4h, while CRO_T117711 was 213

repressed (Fig. 2C). Next, we cloned the CRO_T134526 promoter to drive the expression of the 214

GUS reporter gene. Two light-dependent (D4H and DAT) and a light-independent (CaMV35S) 215

promoters driving the expression of GUS reporter were used as controls. The promoter-GUS 216

reporter plasmids were used for Agro-infiltration of Nicotiana benthamiana leaves. GUS 217

activities were measured in discs of infiltrated leaves collected from dark or light incubated 218

plants. As shown in Fig. 2D, the GUS activity in light-treated leaves, infiltrated with CrGATA1-219

GUS, D4H-GUS or DAT-GUS, was significantly (3-4-fold) higher than that of the dark incubated 220

plants; however, we did not observe significant change of GUS activity in CaMV35S-GUS-221

infiltrated leaves of light or dark incubated plants, suggesting that the CRO_T134526 promoter is 222

light inducible. We selected CRO_T134526, hereafter designated as CrGATA1, for further 223

characterization and to elucidate its regulatory role in light-regulated vindoline biosynthesis. 224

225

Phylogenetic analysis showed that CrGATA1 is in the same clade with the light-inducible 226

Arabidopsis GATA TFs GNC and GNL (Supplemental Fig. S4) (Manfield et al., 2007; 227

Behringer and Schwechheimer, 2015). Like GNC and GNL, CrGATA1 belongs to LLM-domain 228

containing B-GATAs. Amino acid sequence alignment revealed that CrGATA1 shares 39-41% 229

sequence identity with Arabidopsis GATA TFs, GNC and GNL (Supplemental Fig. S5). To 230

determine the sub-cellular localization, CrGATA1 was fused in-frame to eGFP (enhanced GFP), 231

and the fusion gene was expressed in tobacco (N. tabacum) protoplasts. While the control eGFP 232

accumulated throughout the cell, CrGATA1-eGFP fusion protein was localized to the nucleus 233

(Fig. 2E). 234

235

Transient overexpression of CrGATA1 enhances vindoline production in C. roseus seedlings 236

To determine the role of CrGATA1 in vindoline biosynthesis, we transiently overexpressed 237

CrGATA1 in C. roseus seedlings using the FAST method (Weaver et al., 2014). Expression of 238

CrGATA1 and the five light-responsive vindoline pathway genes were measured in the aerial 239

parts of young seedlings infiltrated either with the empty-vector control pCAMBIA1300 (EV) or 240

the overexpression-vector pCAMBIA1300-CrGATA1 (CrGATA1-OX). The RT-qPCR results 241

reveled that, compared to EV, CrGATA1 overexpression resulted in 2.5- to 5-fold increase in the 242

expression of T16H2, D4H, and DAT; expression of T3O and T3R remained unchanged (Fig. 3A). 243



9

In addition, vindoline accumulation was significantly increased, while tabersonine was decreased, 244

in CrGATA1-OX seedlings relative to EV seedlings (Fig. 3B). These findings suggest that 245

CrGATA1 is a positive regulator of vindoline biosynthesis in C. roseus. 246

247

VIGS of CrGATA1 reduces vindoline biosynthesis in C. roseus leaves 248

VIGS was used to repress CrGATA1 expression in C. roseus leaves as previously described 249

(Liscombe and O’Connor, 2011). Expression of CrGATA1 and the five light-responsive 250

vindoline pathway genes were measured in young leaves of C. roseus plants inoculated either 251

with the pTRV2 empty-vector control (EV) or the VIGS vector pTRV2-CrGATA1 (CrGATA1-252

VIGS). We observed that CrGATA1 expression was repressed approximately by 63% in VIGS 253

leaves compared to the EV control (Fig. 3C). In addition, transcript levels of T3O, T3R, and DAT 254

were reduced by 43% - 58% in VIGS leaves compared to EV (Fig. 3C). Expression of T16H2 255

and D4H were not significantly affected in CrGATA1 VIGS lines. Moreover, the amount of 256

tabersonine was significantly elevated while vindoline was decreased in leaves of the CrGATA1-257

VIGS plants compared to the EV plants (Fig. 3D). The results further support that CrGATA1 is a 258

positive regulator of vindoline biosynthesis in C. roseus. To determine whether CrGATA1 259

affects expression of the upstream vindoline pathway genes, we measured the expression of TDC 260

and STR in CrGATA1 overexpression and VIGS lines. We did not detect significant changes in 261

transcript levels compared to EV (Supplemental Fig. S6). 262

263

CrGATA1 transactivates the promoters of vindoline pathway genes 264

To determine whether CrGATA1 can directly activate the promoters of vindoline pathway genes, 265

we performed N. benthamiana leaf-based transactivation assays. The promoters of five light-266

inducible vindoline pathway genes were cloned in the binary vector pKYLX71-GUS to drive the 267

expression of GUS gene. The resulting plasmids were mobilized to A. tumefaciens and 268

individually infiltrated into N. benthamiana leaves together with EV (pCAMBIA1300) or 269

pCAMBIA1300-CrGATA1. GUS activity assay showed that transactivation of the T16H2, T3R, 270

T3O, D4H, and DAT promoters by CrGATA1 were 1.8-2.9 folds compared to EV control (Fig. 271

4A), suggesting that the vindoline pathway genes are regulated by CrGATA1 in C. roseus. 272

273

274



10

GATC-motif is crucial for CrGATA1 activation of the D4H promoter 275

Previous studies have demonstrated that GATA TFs bind to both GATA and GATC motifs 276

(Newton et al., 2001; Sugimoto et al., 2003; Xu et al., 2017). The D4H promoter, highly 277

activated by CrGATA1 (Fig. 4A), was thus chosen for identification of potential binding sites of 278

CrGATA1. In silico analysis revealed that the D4H promoter contains two GATA and two 279

GATC motifs (Fig. 4B and C). First, we mutated the core sequence of the two GATA-motifs (-280

431 to -426 and -139 to -134, relative to first ATG in coding frame) to GGCA by PCR-based 281

site-directed mutagenesis (Pattanaik et al., 2010). Mutation of single or both GATA-motifs had 282

no effect on CrGATA1-mediated activation of the D4H promoter (Fig. 4B). However, 283

transactivation of the D4H promoter by CrGATA1 was abolished when both GATC-motifs (-617 284

to -614 and -541 to -538, relative to ATG) were mutated to GAAA, (Fig. 4C), suggesting that 285

GATC-motifs are crucial for activation of the D4H promoter by CrGATA1. 286

287

Phytochrome is likely involved in light-responsive expression of vindoline pathway genes 288

Plants sense red and far-red light signals through the photoreceptor phytochrome (Franklin and 289

Quail, 2010). Previous studies have shown that the red-light induced enzymatic activities of D4H 290

and DAT in C. roseus seedlings are reversed by far-red light (Aerts and De Luca, 1992; 291

Vazquez-Flota and De Luca, 1998), suggesting a phytochrome-dependent regulation of vindoline 292

biosynthesis. To test this hypothesis, expression of CrGATA1 and five light-inducible vindoline 293

pathway genes were monitored in C. roseus seedlings exposed red and then far-red light for 294

different durations. We used C. roseus ChlH, PORC and RCA as experimental controls, as their 295

orthologs in Arabidopsis and rice respond to red and far-red light in a phytochrome-dependent 296

manner (Liu et al., 1996; Moon et al., 2008; Inagaki et al., 2015) (Fig. 5). Gene expression 297

analysis showed that red light significantly induced the expression of CrGATA1 and vindoline 298

pathway genes, except for D4H (Fig. 5). The red light-mediated induction of vindoline pathway 299

genes was reversed following a two-hour exposure to far-red light (Fig. 5), suggesting the 300

involvement of phytochrome-dependent regulatory factors in the vindoline pathway. 301

302

CrPIF1 represses vindoline pathway gene expression and alkaloid accumulation in C. 303

roseus seedlings 304

PIFs act as negative regulators in light signaling pathway. PIF accumulates in dark and degrades 305



11

upon interaction with phytochromes in light (Pham et al., 2018). We thus asked whether C. 306

roseus PIFs are involved in the light regulation of vindoline biosynthesis. We identified three 307

putative PIFs in the C. roseus genome, designated here as CrPIF1, CrPIF3 and CrPIF4/5. CrPIFs 308

share 35-41% amino acid sequence identity with Arabidopsis PIF1, PIF3 and PIF4, while they 309

share 52-60% identity with tomato PIFs (Supplemental Fig. S7). In addition, C. roseus PIFs are 310

phylogenetically closer to tomato PIFs than those of Arabidopsis (Supplemental Fig. S8). Amino 311

acid sequence alignment of PIFs (Supplemental Fig. S7) showed that all three CrPIFs contain the 312

conserved bipartite nucleus localization signal (NLS) and phytochrome B binding (APB) motif, 313

indicating their conserved regulatory roles in phytochrome-PIF pathway in plants. Simiar to the 314

tomato PIFs (Rosado et al., 2016), CrPIFs appeared to be also regulated at transcriptional level 315

as their expression were affected by light (Supplemental Fig. S9). To determine the regulatory 316

roles of CrPIFs in vindoline biosynthesis, CrPIFs were individually overexpressed in C. roseus 317

seedlings using the FAST method. CrPIF1 overexpression resulted in significant downregulation 318

of CrGATA1 and the light-responsive vindoline pathway genes in dark (Fig. 6A). However, 319

CrPIF3 or CrPIF4/5 had no effects on the expression of CrGATA1 and the vindoline pathway 320

genes (Supplemental Fig. S10). In addition, overexpression of CrPIF1 resulted in increased 321

tabersonine and decreased vindoline (Fig. 6B), indicating that CrPIF1 acts a negative regulator of 322

vindoline biosynthesis in C. roseus. To determine the sub-cellular localization, CrPIF1 was 323

fused in-frame to eGFP (enhanced GFP), and the resulting CrPIF1-eGPF was expressed in 324

tobacco protoplasts. While the control eGFP accumulated throughout the cell, the CrPIF1-eGFP 325

fusion protein was localized to the nucleus (Fig. 6E). 326

327

VIGS of CrPIF1 increases vindoline biosynthesis in C. roseus leaves 328

VIGS was used to repress CrPIF1 expression in young C. roseus leaves. Expression of CrPIF1, 329

CrGATA1, and the five light-responsive vindoline pathway genes (T16H2, T3O, T3R, D4H, and 330

DAT) were measured in leaves of the dark-incubated VIGS plants. Plants inoculated with the 331

pTRV2 empty-vector (EV) served as control. CrPIF1 expression was repressed by approximately 332

70% in VIGS leaves compared to the EV control (Fig. 6C). CrPIF1-silencing resulted in 333

upregulation of CrGATA1 and five vindoline pathway genes by 2-8 folds in VIGS lines 334

compared to EV (Fig. 6C). Moreover, the amount of vindoline was elevated in leaves of the 335

CrPIF1-VIGS plants compared to the EV plants (Fig. 6D). These results further suggest that 336



12

CrPIF1 is a negative regulator of vindoline biosynthesis in C. roseus seedlings. 337

CrPIF1 represses CrGATA1 and DAT through binding to the G/E/PBE-box 338

To determine whether CrGATA1 and the vindoline pathway genes are regulated by CrPIF1, we 339

performed transactivation assays in N. benthamiana leaves. The CrGATA1 promoter was cloned 340

into the plasmid pKYLX71-GUS to drive the expression of GUS gene. The GUS reporter 341

plasmids driven by the promoters of CrGATA1 and five vindoline pathway genes were 342

individually infiltrated into N. benthamiana leaves together with either EV (pCAMBIA1300) or 343

pCAMBIA1300-CrPIF1. We observed that promoter activities of CrGATA1, T16H2, and DAT 344

were significantly repressed (40-50%) by CrPIF1 in dark (Fig. 6F), suggesting that CrPIF1 is a 345

repressor of the vindoline pathway. It is well documented that PIFs bind to G-box (CACGTG) or 346

PBE-box (CACATG/CATGTG) in the target promoters (Zhang et al., 2013). We identified a G-347

box (-142 to -137 relative to first ATG) in the CrGATA1 promoter (Fig. 6G) and a PBE-box (-348

1106 to -1101 relative to first ATG) in DAT promoter (Fig. 6H). The G-box in the CrGATA1 349

promoter and PBE-box (CACATG) in the DAT promoter were mutated to CAAAAG and 350

CACAAA, respectively. Transactivation assays using N. benthamiana leaves were performed to 351

evaluate the effects of CrPIF1 on the mutated CrGATA1 and DAT promoters. We found that the 352

repressive effect of CrPIF1 on the CrGATA1 and DAT promoters was abolished by mutations in 353

G-box and PBE-box, respectively (Fig. 6G and 6H). These findings suggest that CrPIF1 354

represses the activities of CrGATA1 and DAT likely by binding to the G-box or PBE-box motifs 355

in the promoters. 356

357

DISCUSSION 358

TIA biosynthesis in C. roseus is a highly complex and elaborated process that involves more than 359

30 different enzymes, multiple cell types and sub-cellular compartments. A number of TFs 360

regulating biosynthesis of TIAs, such as strictosidine that serve as precursor of tabersonine and 361

catharanthine, have been characterized (Menke et al., 1999; van der Fits and Memelink, 2000; 362

Suttipanta et al. 2011; Zhang et al., 2011; Pan et al., 2012; Li et al., 2013; Van Moerkercke et al., 363

2015; Van Moerkercke et al., 2016; Paul et al., 2017; Patra et al., 2018; Schweizer et al., 2018; 364

Sui et al. 2018). By comparison, our knowledge on transcriptional regulation of the vindoline 365

pathway and light-mediated TIA biosynthesis is extremely limited. Here, we identified and 366

characterized CrGATA1 and CrPIF1 for their roles in regulating vindoline biosynthesis in C. 367



13

roseus seedlings. 368

369

TIA biosynthesis is developmentally regulated and is influenced by environmental cues, such as 370

light. Tabersonine is present in both leaves and roots, whereas vindoline is predominantly found 371

in leaves (De Luca et al., 1986). Moreover, dark-grown, etiolated C. roseus seedlings accumulate 372

trace amount of vindoline which increases upon exposure to light. Correspondingly, the dark-373

grown seedlings accumulate a significant amount of tabersonine which declines upon exposure 374

to light (De Luca et al. 1986). In addition, light induces the expression of D4H and DAT and their 375

enzymatic activities in C. roseus seedlings (De Luca et al., 1986; De Carolis et al., 1990; 376

Vazquez-Flota and De Luca, 1998; St-Pierre et al., 1998). Our gene expression analysis revealed 377

that, in addition to D4H and DAT, expression of T16H2, T3O, and T3R are significantly induced 378

by light in C. roseus seedlings (Fig. 1A). In addition, the increase of vindoline accumulation is 379

accompanied by the decrease of tabersonine upon exposure to light (Fig. 1B), further confirming 380

the role of light in vindoline biosynthesis in C. roseus seedlings. Light is also known to affect the 381

biosynthesis of other specialized metabolites, including SGA in tomato (Wang et al., 2018) and 382

anthocyanins in a number of plant species (Liu et al. 2018). Consistent with leaf-specific 383

vindoline accumulation, CrGATA1 and the five light-responsive vindoline pathway genes are 384

preferentially expressed in areal parts of the seedling (Fig. 2A). The leaf-specific expression of 385

CrGATA1 and the vindoline pathway genes relative to those in roots (Fig. 2A) are significantly 386

higher than light-induced expression in the seedling (Fig. 1A and Fig. 2B), because the basal 387

expression of these genes in roots are extremely low. 388

Cis-regulatory elements present in the gene promoters of metabolic pathways often provide clues 389

about the potential TFs involved in the regulatory network and have been used as a tool for 390

identification of regulators. For instance, CrMYC2 was initially isolated using the G-box element 391

present in C. roseus STR promoter and later demonstrated as a regulator of TIA biosynthesis 392

(Zhang et al. 2011; Schweizer et al., 2018; Sui et al. 2018). The presence of AT-rich motifs in the 393

jasmonate-responsive element (JRE) of the ORCA3 promoter led to the identification of the AT-394

hook regulators in C. roseus (Vom Endt et al., 2007). In addition, presence of putative MYB 395

binding sites in a betalain pathway gene promoter (Polturak and Aharoni, 2018) and G-box/G-396

box-like sequences in tomato SGA biosynthetic pathway genes (Cárdenas et al., 2016) indicate 397

the possible involvement of MYBs and MYC2, respectively, in the pathway regulations. Two 398



14

R2R3 MYBs have since been identified as regulators of betalain biosynthesis in beet (Polturak 399

and Aharoni, 2018). Our analysis of the vindoline pathway gene promoters revealed the presence 400

of a number of light-responsive elements, including the GATA/GATC and G/E-box motifs 401

(Supplementary Table S1). The presence of GATA/GATC motifs in the five light-responsive 402

promoters in vindoline biosynthetic pathway led us to speculate that GATA family TFs are 403

involved in the light regulation of vindoline biosynthesis. In addition, we noticed the presence of 404

G/E-box that are recognized by bHLH TFs, including PIFs, that are known to be involved in 405

light-responsive gene expression in plants (Yadav et al., 2005; Pham et al., 2018). 406

407

Transcriptomic and genomic resources are invaluable for identification of missing genes 408

encoding key enzymes, transporters, and regulatory proteins in C. roseus (Geu-Flores et al., 2012; 409

Van Moerkercke et al., 2015; Larsen et al., 2017; Paul et al. 2017; Payne et al., 2017; Caputi et al. 410

2018; Patra et al. 2018; Qu et al. 2019). Co-expression analysis of vindoline biosynthetic 411

pathway genes and GATA TFs identified two putative candidates for further characterization 412

(Supplemental Fig. S3). Similar to the vindoline pathway genes (Vazquez-Flota et al., 1997; St-413

Pierre et al., 1998; Besseau et al., 2013), CrGATA1 is preferentially expressed in leaves (Fig. 2A) 414

and significantly induced by light (Fig. 2B). Transient overexpression and VIGS of CrGATA1 415

significantly altered the expression of most of the vindoline pathway genes and vindoline 416

accumulation in C. roseus (Fig. 3). Expression of T3O and T3R were not increased in CrGATA1 417

overexpression while expression of T16H2 and D4H did not significantly change in VIGS lines. 418

These observations suggest that other regulators are also involved in the gene regulation. Similar 419

observations have been made for other regulators in the TIA pathway. For instance, a previous 420

study has shown that Catharanthus MYC2 (CrMYC2) regulates the AP2/ERF, ORCA3, by 421

binding to the T/G-box motif in the promoter. However, CrMYC2 overexpression does not 422

significantly affect ORCA3 transcripts, whereas silencing CrMYC2 in Catharanthus cells reduces 423

ORCA3 expression (Zhang et al., 2011). Similarly, ORCA3 is known to regulate the expression 424

of TDC. However, overexpression of ORCA3 in C. roseus hairy roots does not significantly 425

induce TDC expression (Peebles et al., 2009). Expression of TDC and STR were not affected by 426

overexpression or VIGS of CrGATA1, indicating that CrGATA1 does not regulate the upstream 427

TIA pathway genes in C. roseus seedlings. 428

Transactivation assay in N. benthamiana leaves showed that CrGATA1 activates the promoters 429



15

of key vindoline pathway genes (Fig. 4), suggesting that CrGATA1 is an activator in vindoline 430

biosynthesis. GATA TFs are involved in a number of developmental and physiological processes. 431

However, little is known about the roles of GATA TFs in light regulation of specialized 432

metabolism. Two well-characterized Arabidopsis GATA TFs, GNC and GNL, are light-inducible 433

and involved in chloroplast biogenesis and nitrogen metabolism (Richter et al., 2010; Hudson et 434

al., 2011). GNC and GNL bind the GATA motif in the GLU1 promoter (Hudson et al., 2011), 435

whereas the tobacco GATA TF, AGP1 activates NtMYC2 by binding to the GATC motif in the 436

NtMYC2 promoter (Sugimoto et al., 2003). Moreover, genome-wide binding analysis of GNC 437

and GNL reveals that both GATA and GATC cis-elements are enriched in the targets (Xu et al., 438

2017). We identified multiple GATA and GATC cis-elements in the promoters of DAT, D4H, T3R, 439

T3O, and T16H2. Mutation to the GATC element, but not the GATA element (Fig. 4B), in the 440

D4H promoter had a significant effect on the transactivation (Fig. 4C), suggesting that CrGATA1 441

likely recognizes the GATC element in activation of D4H. 442

443

Activities of D4H and DAT increase significantly upon exposure of C. roseus seedlings to red 444

light, and the effect is reversed by far-red light (Aerts and De Luca, 1992; Vazquez-Flota and De 445

Luca, 1998). In addition, transcript levels of D4H increase following exposure to red light 446

(Vazquez-Flota and De Luca, 1998). Phytochromes serve as receptors of red and far-red light in 447

plants and exist in two different forms, the inactive Pr and active Pfr. In the absence of red light, 448

the inactive Pr accumulates in cytosol; however, upon perception of red light, Pr converts to the 449

active Pfr that is subsequently translocated to the nucleus (Franklin and Quail, 2010). Here we 450

demonstrated that expression of CrGATA1, T16H2, T3O, T3R, and DAT in C. roseus seedling 451

increase upon exposure to red light and decrease following exposure to far-red light (Fig. 5), 452

suggesting a phytochrome-dependent regulation of vindoline biosynthesis. We did not observe an 453

apparent increase in D4H expression upon exposure to red light. This is most likely due to the 454

duration of treatment that affects its expression in seedlings. PIFs are known to interact with 455

phytochromes and regulate light-responsive gene expression in plants. PIFs regulate biosynthesis 456

of specialized metabolites, including anthocyanins (Shin et al., 2007; Liu et al., 2015) and SGAs 457

(Wang et al., 2018). For anthocyanins biosynthesis in Arabidopsis, PIF3 and HY5 act as 458

activators (Shin et al., 2007), whereas PIF4 and PIF5 function as repressors as overexpression of 459

PIF4 or PIF5 reduces anthocyanin accumulation (Liu et al., 2015). We identified three putative 460



16

PIFs in C. roseus genome. Transient overexpression or VIGS of CrPIF1 altered vindoline 461

pathway gene expression and vindoline accumulation in C. roseus seedlings (Fig. 6A-D). 462

Previous studies demonstrate that PIFs bind to the G/E-box/PBE elements in the target promoters. 463

Scanning of the promoters of CrGATA1 and vindoline pathway genes revealed the presence of 464

putative PIF binding sites (Fig. 6G and H). Transient transactivation assays showed that CrPIF1 465

repressed the promoter activities of CrGATA1 and vindoline pathway genes (Fig. 6G and H). 466

Site-directed mutagenesis of the PIF binding sites in the CrGATA1 and DAT promoters abolished 467

PIF-mediated repression, suggesting that CrPIF1 directly regulates CrGATA1 and DAT by 468

binding to the G/E-box/PBE elements in the promoters. The T16H2 promoter does not contain 469

canonical PBE (CACATG) motifs, but contains three E-box motifs (CAAATG, CAATTG and 470

CAGCTG) that are highly similar to the PBE. CrPIF1 likely suppresses T16H2 expression by 471

binding to the E-box (Fig. 6A). As TIA accumulation in C. roseus is developmentally regulated, 472

the difference in the alkaloid contents observed in this study between overexpression (Fig. 3B, 473

6B) and VIGS (Fig. 3D, 6D) lines of CrGATA1 or CrPIF1 is likely due to the age of the 474

seedlings used in the experiments. 475

476

In conclusion, our work elucidates a mechanism by which light influences vindoline biosynthesis 477

through the newly characterized CrGATA1 and CrPIF1. CrPIF1 represses the expression of 478

CrGATA1 and vindoline pathway genes in the dark, resulting in reduced vindoline accumulation. 479

CrPIF1 is possibly degraded in light by the 26S/UPS, leading to de-repression of CrGATA1. The 480

activation of CrGATA1 leads to upregulation of the vindoline pathway genes and increased 481

vindoline accumulation in C. roseus seedlings (Fig. 7). Other regulators are likely also involved 482

in vindoline biosynthesis. It remains unclear what transactivator regulates CrGATA1, which, 483

despite repression by CrPIF1, expresses at low (basal) level in the dark. Consequently, trace 484

amounts of vindoline can be detected in dark-grown C. roseus seedlings. Nevertheless, our 485

findings revealed a previously uncharacterized molecular mechanism that controls light-486

mediated TIA biosynthesis in C. roseus. The roles of PIF-mediated GATA TF regulation is 487

perhaps generally conserved in plant light-regulated biosynthesis of specialized metabolites. 488

489

MATERIALS and METHODS 490

491



17

Plant materials, growth condition and treatments 492

Catharanthus roseus (L.) G. Don var. ‘Little Bright Eye’ seeds obtained from NESeed 493

(neseed.com) were surface-sterilized using 30% (v/v) commercial bleach for 6 minutes, rinsed 494

five times with sterile water and incubated in dark at 28°C for germination on half-strength MS 495

medium. Seven-day-old etiolated seedlings were treated with white light (40 μmol m-2

s-1

), red 496

light (31 μmol m-2

s-1

) or far-red light (52 μmol m-2

s-1

). For white light treatment, seedlings were 497

incubated for 1, 4, 10, 24, 48 or 96 hours. For red and red/far-red light treatments, the seedlings 498

were exposed to red light for 2 and 4 hr, and then exposed to far-red light for two hours. Aerial 499

parts of seedlings were collected for RNA isolation or alkaloid extraction. 500

501

RNA isolation, cDNA synthesis and quantitative RT-PCR 502

RNA isolation, cDNA synthesis and quantitative reverse-transcription PCR (RT-qPCR) were 503

performed as previously described (Paul et al., 2017). Primers used in RT-qPCR are listed in 504

Table S2. 505

506

In Silico analysis of putative regulators of vindoline in C. roseus 507

To identify C. roseus GATA TFs, sequences of all protein-coding genes were downloaded from 508

the latest version of the C. roseus genome from Dryad Digital Repository (Kellner et al., 2015). 509

BLAST search was preformed to identify the putative GATA and PIF TFs. To further validate 510

the BLAST search results, phylogenetic trees were constructed and visualized using Neighbor-511

Joining (N-J) method through MEGA5.1 software (Tamura et al., 2011). The statistical reliability 512

of individual nodes of the newly constructed trees was assessed by bootstrap analyses with 1,000 513

replications (Altschul et al., 1997). Alignments of amino acids were conducted by MAFFT 514

method (Katoh and Standley, 2013). 515

To analyze the expression patterns of C. roseus GATAs and vindoline pathway genes in five 516

different tissues (seedling, mature leaf, immature leaf, stem and root) (Góngora-Castillo et al., 517

2012), hierarchical clustering was performed as previously described (Paul et al., 2017). 518

519

520

Sub-cellular localization 521

To determine the sub-cellular localization of CrGATA1 or CrPIF1, full-length cDNA was 522



18

translationally fused with N-terminus of enhanced GFP (eGFP) in a pBlueScript (pBS) plasmid 523

as described earlier (Suttipanta et al., 2011). Expression of eGFP was driven by the CaMV 35S 524

promoter and the rbcS terminator. Plasmids were electroporated into tobacco (N. tabacum) 525

protoplasts and visualized with a fluorescence microscope (Nikon Eclipse TE200, Nikon Corp.) 526

after 20 h of incubation in dark at room temperature. A pBS plasmid expressing only eGFP 527

served as a negative control. 528

529

Plasmid construction and transient gene overexpression in C. roseus seedling 530

For transient overexpression in C. roseus seedlings, CrGATA1, CrPIF1, CrPIF3 or CrPIF4/5 531

were cloned into a modified pCAMBIA1300 vector containing CaMV35S promoter and rbcS 532

terminator. C. roseus seedlings were transiently transformed with the plasmids using the Fast 533

Agro-mediated Seedling Transformation (FAST) method with some modifications (Weaver et al. 534

2014). Briefly, Agrobacterium tumefaciens GV3101 harboring the plasmid was grown on Luria-535

Bertani (LB) plates containing 100 µg ml−1

kanamycin, 50 µg ml−1

gentamicin and 30 µg ml−1

536

rifampicin. A single colony was transferred to 2 ml liquid LB medium containing same 537

antibiotics and incubated at 250 rpm and 28°C. Overnight grown Agrobacterium cells were sub-538

cultured in 20 ml liquid LB medium for 16 h at 250 rpm and 28°C. Agrobacterium cultures were 539

then centrifuged and the pellet was resuspended in infiltration buffer (10 mM MgCl2, 10 mM 540

MES, 100 µM acetosyringone) at an OD600 of 1.0, followed by incubation at 28°C for at least 3 h. 541

Seven-day-old C. roseus seedlings were immersed in the Agrobacterium cultures for 1 h. After 542

infiltration, seedlings were washed with sterile distilled water for five times and laid on petri 543

dishes with autoclaved wet filter papers. After three days, aerial parts of seedlings were collected 544

for RNA extraction and alkaloid analyses. 545

546

Virus-induced gene silencing in C. roseus plants 547

For virus-induced gene silencing (VIGS) (Liu et al., 2002), the plasmids pTRV2-CrChlH, 548

pTRV2-CrGATA1 and pTRV2-CrPIF1 were generated by cloning partial coding sequences of 549

CrChlH (400 bp) or CrGATA1 (358 bp) or CrPIF1 (183 bp) in the multiple cloning sites (MCS) 550

of pTRV2 vector. C. roseus seedlings with two pairs of true leaves were used to perform the 551

VIGS assay using pinch method as previously described (Liscombe and O’Connor, 2011). 552

Harvest time was guided by the appearance of photobleaching of the corresponding leaves in 553



19

which CrChlH was silenced. As a control, plants were infected with an empty pTRV2 vector 554

(EV). The newly emerging pair of leaves following inoculation were harvested, frozen in liquid 555

nitrogen, and then stored in -80 °C until RNA and alkaloid extraction. 556

557

Plasmid construction and Nicotiana benthamiana leaf infiltration assays 558

The reporter plasmids for N. benthamiana leaf infiltration assays were generated by replacing the 559

CaMV 35S promoter in a modified pKYLX71 vector containing the GUS reporter and rbcS 560

terminator (Schardl et al., 1987) with T16H2 (1129 bp), T3O (703 bp), T3R (1129 bp), D4H (704 561

bp), DAT (1317 bp) or CrGATA1 (1189 bp) promoter. Mutants of the following cis-elements, 562

GATA-motifs (-430 to -427, and -138 to -135) and GATC-motifs in D4H promoter (-617 to -614, 563

and -541 to -538), G-box in CrGATA1 promoter (-142 to -137) and PBE-box in DAT promoter (-564

1106 to -1101) were generated by site-directed mutagenesis (Pattanaik et al., 2010). 565

pCAMBIA1300 vectors containing CrGATA1 or CrPIF1 were used as the effector plasmids. A 566

firefly luciferase (LUC) reporter, driven by CaMV 35S promoter and rbcS terminator, was used 567

as an internal control in the leaf infiltration assays. Infiltration solutions were prepared as 568

described in FAST method. Before infiltration, effector, reporter and internal control solutions 569

were combined at 1:1:1 ratios and mixed well. Infiltration of N. benthamiana leaves was 570

performed as previously described (Kumar and Bhatia, 2016). Two days after infiltration, leaf 571

discs were collected, frozen in liquid nitrogen and ground to powder for protein extraction. LUC 572

and GUS activities were measured as previously described (Pattanaik et al., 2010). 573

574

Alkaloid extraction and analysis 575

To extract alkaloids, light-treated seedlings, Agro-infiltrated seedlings or leaves collected for 576

VIGS assay were frozen in liquid nitrogen and ground to powder. Samples were extracted twice 577

in methanol (1:100 w/v) for 24 h on a shaker. Pooled extracts were dried using a rotary 578

evaporator and diluted in methanol. Samples were analyzed with high-performance liquid 579

chromatography (HPLC), followed by electrospray-injection in tandem mass spectrometry, as 580

described previously (Suttipanta et al., 2011). The concentrations of the alkaloids were 581

calculated using standard curve. 582

583

ACCESSION NUMBERS 584



20

CrGATA1 (MK801106), CrPIF1 (ALI87040.1), CrPIF3 (ALI87041.1) and CrPIF4/5 585

(ALI87042.1) 586

587

SUPPLEMENTAL DATA 588

Supplemental Figure S1. Simplified TIA biosynthetic pathway in C. roseus. 589

Supplemental Figure S2. Gene expression analysis and measurement of TIAs in C. roseus 590

seedlings. 591

Supplemental Figure S3. Co-expression of CrGATA genes with five light-inducible vindoline 592

pathway genes in different tissues of C. roseus. 593

Supplemental Figure S4. Phylogenetic analysis of AtGATAs and CrGATAs. 594

Supplemental Figure S5. Multiple sequence alignment of CrGATA1, and Arabidopsis GNC and 595

GNL. 596

Supplemental Figure S6. TDC and STR expression are not altered in CrGATA1 overexpression 597

and VIGS lines. 598

Supplemental Figure S7. Amino acid sequence alignment of PIFs from C. roseus, Arabidopsis, 599

and tomato. 600

Supplemental Figure S8. Phylogenetic analysis of PIFs from C. roseus, Arabidopsis and tomato. 601

Supplemental Figure S9. Expression of CrPIFs in response to light and dark. 602

Supplemental Figure S10. CrGATA1 and vindoline pathway genes are not altered by CrPIF3 and 603

CrPIF4/5 overexpression in C. roseus seedlings. 604

Supplemental Table S1. Light responsive cis-elements within promoters of five light-induced 605

vindoline. 606

Supplemental Tables S2. Primers used in this study. 607

608

609

ACKNOWLEDGEMENTS 610

We thank Dr. Bruce Downie of Department of Horticulture, University of Kentucky for 611

assistance and advice on red/far-red light treatment of C. roseus seedlings, Mr. J. May and Ms. M. 612

Combs (Department of Civil Engineering and Environmental Research Training Laboratories, 613

University of Kentucky) for assistance on LC-MS/MS. This work is supported partially by the 614

Harold R. Burton Endowed Professorship to L.Y. and by the National Science Foundation under 615

Cooperative Agreement no. 1355438 to L.Y. 616

617

Figure legends 618

Figure 1. Light-induced expression of vindoline pathway genes and vindoline production in 619

C. roseus seedlings. (A) Relative expression levels of seven vindoline pathway genes in aerial 620

parts of C. roseus seedlings. Seven-day-old, dark-grown, etiolated seedlings were exposed to 621

white light for different lengths of time (1 h, 4 h, 10 h, 24 h, 48 h, 96 h). Transcript levels of 622



21

T16H2, 16OMT, T3O, T3R, NMT, D4H and DAT were measured by RT-qPCR. The RPS9 gene 623

was used as an internal reference gene. (B) Accumulation of tabersonine and vindoline in aerial 624

parts of C. roseus seedlings. Here, “0 hour” refers to seven-day-old etiolated seedlings, which 625

were growing in dark (control) and then exposed to white light for 24 h and 96 h. Alkaloids were 626

extracted and analyzed by LC-MS/MS, and the concentrations of the alkaloids were estimated 627

based on peak areas compared to standards. Values represent means ± standard deviation from 628

three biological replicates. For each replicate, 8-10 seedlings were combined. Statistical 629

significance was determined by the Student’s t test (* P < 0.05; ** P < 0.01). 630

631

Figure 2. Identification of CrGATA1. (A) Expression of CRO_134526 (CrGATA1), 632

CRO_117711 and five light inducible vindoline pathway genes in aerial parts and roots of seven-633

day-old light-grown C. roseus seedlings. (B) Expression of CRO_134526 (CrGATA1) is quickly 634

induced while (C) CRO_117711 is repressed by light in areal parts of C. roseus seedlings. For 635

light treatment, seven-day-old etiolated seedlings were exposed to white light for different 636

lengths if time. Transcript levels of vindoline pathway genes, CrGATA1 and CRO_117711 were 637

measured by RT-qPCR with RPS9 as internal reference gene. (D) D4H, DAT and CrGATA1 638

promoters are light inducible in N. benthamiana leaf. CaMV35S promoter is used as negative 639

control. D4H, DAT and CrGATA1 promoters were cloned in pKYLX71 vector, respectively, to 640

drive the expression of GUS gene. The promoter-GUS plasmids were infiltrated in N. 641

benthamiana leaves. Plants were kept in dark or light for three days. GUS activities were 642

normalized by luciferase activities. Values represent means ± SD from three biological replicates. 643

Statistical significance was determined by the Student’s t test (** P < 0.01). (E) eGFP is 644

accumulated throughout the cell (left) whereas eGFP-CrGATA1 is localized to the nucleus 645

(right). The experiment was repeated two times and a representative result is shown here. 646

647

Figure 3. CrGATA1 positively regulates vindoline biosynthesis in C. roseus. Transient 648

overexpression of CrGATA1 in C. roseus seedlings elevates expression of vindoline pathway 649

genes (A) and vindoline production (B). (A) Relative expression of CrGATA1 and five light-650

inducible vindoline pathway genes in empty vector (EV) controls and CrGATA1 overexpression 651

(OX) seedlings measured by RT-qPCR. (B) Measurement of tabersonine and vindoline in EV 652

controls and CrGATA1 OX lines. (C) Expression of vindoline pathway genes in CrGATA1 VIGS 653



22

leaves. Relative expression of CrGATA1 and five light-inducible vindoline pathway genes in 654

empty vector (EV) controls and CrGATA1 VIGS leaves were measured by RT-qPCR. (D) 655

Measurement of tabersonine and vindoline in EV controls and CrGATA1 VIGS lines. Alkaloids 656

were extracted and analyzed by LC-MS/MS, and the concentrations of the alkaloids were 657

estimated based on peak areas compared to standards. For RT-qPCR, The RPS9 gene was used 658

as an internal reference gene. In all cases, values represent means ± SD from three biological 659

replicates. Statistical significance was calculated using the Student’s t-test (* P < 0.05; ** P < 660

0.01). 661

662

Figure 4. CrGATA1 transactivates promoters of five light-inducible vindoline pathway 663

genes through GATC-motifs. (A) Transactivation of T16H2, T3O, T3R, D4H and DAT 664

promoters (-pro), fused to the GUS reporter, by CrGATA1. Effector (CrGATA1) and reporter 665

(promoter-GUS) constructs were co-infiltrated into N. benthamiana leaves. A plasmid containing 666

luciferase reporter, driven by CaMV35S promoter and rbcS terminator, was used as a 667

normalization control. Luciferase and GUS activities were measured two days after infiltration. 668

GUS activity was normalized against luciferase activity. Control represents the reporter with 669

empty vector (EV). (B) Schematic diagram showing the GATA-motifs in the D4H promoter. 670

Point mutations in the GATA-motifs are indicated by red letters. Mutation in the GATA-motif 671

has no effects on the activation of the D4H promoter by CrGATA1. (C) Schematic diagram 672

showing the GATC-motifs in the D4H promoter. Mutations in the GATC-motifs are indicated by 673

red letters. Mutation in the GATC-motif affects the activation of the D4H promoter by 674

CrGATA1. Data presented here are the means ± SD of three biological replicates. Statistical 675

significance was calculated using the Student’s t-test (* P < 0.05; ** P < 0.01). 676

Figure 5. Expression of CrGATA1 and five light-inducible vindoline pathway genes in C. 677

roseus seedlings exposed to red and far-red light. Seven-day-old etiolated C. roseus seedlings 678

were treated with red light for 4 h (measured at 2 h and 4 h), followed by far-red light for 2 h. 679

Gene expression in aerial parts of the seedlings was measured by RT-qPCR. The CrChlH, 680

CrPORC and CrRCA were used as positive controls. The RPS9 gene was used as an internal 681

reference gene. Data represent means ± standard deviation of three biological samples. Different 682

letters denote statistical differences as assessed by one-way ANOVA and Tukey HSD (P < 0.05). 683

684



23

Figure 6. CrPIF1 negatively regulates CrGATA1 and vindoline pathway genes through G-685

box or PBE box. (A) Relative expression of CrGATA1 and five light-inducible vindoline 686

pathway genes in empty vector (EV) controls and CrPIF1 overexpression (OX) seedlings were 687

measured by RT-qPCR. Seven-day-old seedlings were infiltrated and kept in dark for three days 688

before sample collection. (B) Measurement of tabersonine and vindoline in EV controls and 689

CrPIF1 OX lines. (C) Expression of CrGATA1 and vindoline pathway genes in CrPIF1 VIGS 690

leaves. Relative expression of CrPIF1, CrGATA1 and five vindoline pathway genes in EV and 691

CrGATA1 VIGS leaves were measured by RT-qPCR. (D) Measurement of tabersonine and 692

vindoline in EV controls and CrPIF1 VIGS lines. For RT-qPCR, the RPS9 gene was used as an 693

internal reference gene. For tabersonine and vindoline contents, alkaloids were extracted and 694

analyzed by LC-MS/MS, and the concentrations of the alkaloids were estimated based on peak 695

areas compared to standards. (E) Sub-cellular localization of CrPIF1 in tobacco (N. tabacum) 696

protoplasts. eGFP is accumulated throughout the cell (left) whereas eGFP-CrPIF1 is localized to 697

the nucleus (right). (F) Transactivation of CrGATA1, T16H2, T3O, T3R, D4H and DAT 698

promoters (-pro), fused to the GUS reporter, by CrPIF1. Transactivation assays were carried out 699

by co-infiltration of the CrGATA1-expression vector with a pro-GUS construct into N. 700

benthamiana leaves. The plants were incubated in dark after infiltration. A plasmid containing 701

luciferase reporter, driven by CaMV 35S promoter and rbcS terminator, was used as a 702

normalization control. Luciferase and GUS activities were measured two days after infiltration. 703

GUS activity was normalized against luciferase activity. Control represents the reporter with EV. 704

(G) Mutation in the G-box sequence (top panel) affects the transactivation of the CrGATA1 705

promoter by CrPIF1. (H) Mutation in the PBE-box sequence (top panel) affects the 706

transactivation of the DAT promoter by CrPIF1. All data presented here are the means ± SD of 707

three biological replicates. Statistical significance was calculated using the Student’s t-test (* P < 708

0.05). 709

710

Figure 7. Models depicting the regulatory roles of CrPIF1-CrGATA1 module in light-711

induced of vindoline biosynthesis. Left panel: CrPIF1 is likely accumulated in the dark and 712

represses the expression of CrGATA1, T16H2 and DAT by binding to their promoters. 713

Repression of CrGATA1 results in downregulation of vindoline pathway genes, T16H2, T3O, 714

T3R, D4H and DAT, leading to limited vindoline production and increased tabersonine 715



24

accumulation. One or more unknown TF (TF?) mediates the low (basal) expression of CrGATA1 716

despite CrPIF1 repression. Right panel: CrPIF1 is possibly degraded upon exposure of C. roseus 717

seedlings to light, which is mediated by the red light sensed by phytochrome. De-repression of 718

CrGATA1 results in the activation of vindoline pathway genes and vindoline accumulation. The 719

seven genes involved in conversion of tabersonine to vindoline are listed in the inserted box. 720

Genes in red are responsive to light induction. 721

722

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Xu Z, Casaretto JA, Bi YM, Rothstein SJ (2017) Genome-wide binding analysis of AtGNC and AtCGA1 932 demonstrates their cross‐regulation and common and specific functions. Plant Direct 1: e00016 933

Yadav V, Mallappa C, Gangappa SN, Bhatia S, Chattopadhyay S (2005) A basic helix-loop-helix transcription 934 factor in Arabidopsis, MYC2, acts as a repressor of blue light–mediated photomorphogenic growth. Plant 935 Cell 17: 1953-1966 936

Zhang H, Hedhili S, Montiel G, Zhang Y, Chatel G, Pré M, Gantet P, Memelink J (2011) The basic helix-loop-937

helix transcription factor CrMYC2 controls the jasmonate-responsive expression of the ORCA genes that 938 regulate alkaloid biosynthesis in Catharanthus roseus. Plant J 67: 61-71 939

Zhang Y, Mayba O, Pfeiffer A, Shi H, Tepperman JM, Speed TP, Quail PH (2013) A quartet of PIF bHLH 940 factors provides a transcriptionally centered signaling hub that regulates seedling morphogenesis through 941 differential expression-patterning of shared target genes in Arabidopsis. PLoS Genet 9: e1003244 942

943

944



6 T16H2 16OMT2 9 T3O

6T3R 2 NMT 3 D4H DAT

DarkLight

4

2

0

42

0

1

0

1

0

0

0 0

6

3

2

1

4321

1 4 10 24 48 96Time (h)

A

B

Rel

ativ

e ex

pres

sion

LightDark

0

400

800

1200 Tabersonine Vindoline

0

300

600

900

ng m

g-1

DW

0 24 96 0 24 96

LightDark

8

Time (h) Time (h)

*

***

*

*

**

**

**** ** **

****

**

** ** **

**

** **

**

** ** ****

**

**

**

1 4 10 24 48 96Time (h)

1 4 10 24 48 96Time (h)

1 4 10 24 48 96Time (h)

**

****

**

**



RootsAerial parts

05

10100

10000

20000

30000

40000

Rel

ativ

e ex

pres

sion

**

**

**

**

**

**

**

1 4 10 24 48 96Time (h)

0

1

2

3

4

5

Rel

ativ

e ex

pres

sion

CRO_T134526 (CrGATA1)

**

**

**

**

1 4 10 24 48 96Time (h)

0

1

2 CRO_T117711

Rel

ativ

e ex

pres

sion

****

0

1

2

3

4

5

Rel

ativ

e G

US

activ

ity

eGFP eGFP-CrGATA1

A B

C D

E

DarkLight

DarkLight

**

****

DarkLight



* *

****

0

3

6

Rel

ativ

e ex

pres

sion

Rel

ativ

e ex

pres

sion

0

1

2

**

Tabersonine Vindoline


0

500

1000

1500

2000

ng m

g-1

DW

0204060

20005000

10000

ng m

g-1

DW

*

*

*

**

A B

C D

ControlCrGATA1-OX

ControlCrGATA1-OX

** **

ControlCrGATA1-VIGS

ControlCrGATA1-VIGS



0

1

2

3

4

Rel

ativ

e G

US

activ

ity*

****

***

A

C

EV + promoter-GUSCrGATA1 + promoter-GUS

GATC GATC

GAAA GATC

GATC GAAA

GAAA GAAA

- 617 - 614 - 541 - 538

WT

MUT1

MUT2

M1M2

D4H

-pro

WT MUT1 MUT2 M1M20

1

2

3

4R

elat

ive

GU

S ac

tivity

EV + D4H-pro-GUSCrGATA1 + D4H-pro-GUS

**

*- 1

ATG

ATG

ATG

ATG

B

GATA GATA

GGCA GATA

GATA GGCA

GGCA GGCA

- 430 - 427 - 138 - 135

WT

MUT1

MUT2

M1M2

D4H

-pro

- 1ATG

ATG

ATG

ATGWT MUT1 MUT2 M1M2

0

1

2

3

4

Rel

ativ

e G

US

activ

ity

EV + D4H-pro-GUSCrGATA1 + D4H-pro-GUS

* * * *



CrChlH

D4H DAT

CrGATA1

CrPORC CrRCA

T3O

T3R

T16H2

0

1

2

3

0

1

2

0

1

2

3

Rel

ativ

e ex

pres

sion

0

1

2

0

1

2

3

0

2

4

6

0

1

2

3

0

1

2

0

1

2

0 2 4 6

R FR0 2 4 6

R FR

0 2 4 6

R FR

cb

a

c

b ba

bc

bc

ab

ba a

c ba a

c dc

ab

cb

ab a a a

b

b ba

c

Time (h)



***

EV + promoter-GUSCrPIF1 + promoter-GUS

0

0.5

1.0

1.5

Rel

ativ

e G

US

activ

ity

F

G

CACGTG

- 142 - 137

WT

MUT CAAAAG

CrGATA1 promoter

CACATG

- 1106 - 1101

WT

MUT

DAT promoterH

CACAAA

EV + CrGATA1-pro-GUSCrPIF1 + CrGATA1-pro-GUS

EV + DAT-pro-GUSCrPIF1 + DAT-pro-GUS**

WT MUT WT MUT0

0.5

1.0

1.5

Rel

ativ

e G

US

activ

ity

- 1

ATG

ATG

- 1

ATG

ATG

0

0.5

1

1.5

2

2.5

Rel

ativ

e Ex

pres

sion

Tabersonine Vindoline0

400

800

1200

1600

ng m

g-1D

W

ControlCrPIF1-OX

ControlCrPIF1-OX

*

* * **

*

** **

0

0.5

1.0

Rel

ativ

e G

US

activ

ity 1.5

CrGATA1 T16H2 T3O T3R D4H DAT

A B

0

2

4

6

8

10

Rel

ativ

e Ex

pres

sion

ControlCrPIF1-VIGS

C D

E

**

****

**

**

**

ng m

g-1D

W

0

50

8000

16000

**

*


**

ControlCrPIF1-VIGS

eGFP eGFP-CrPIF1



CrGATA1

CrPIF1

CrPIF1

T3O, T3R, D4H

CrGATA1

CrGATA1

T16H2, DAT

CrPIF1

Red lightCrPIF1

CrPIF1

T16H2, DAT

T16H2, T3O, T3R, D4H, DAT

CrGATA1


Vindoline Tabersonine

TF?

CrGATA1

TF?

Basal activation of CrGATA1Strong activation of CrGATA1

Tabersonine

Vindoline

T16H216OMTT3OT3RNMTD4HDAT



Parsed CitationsAerts RJ, De Luca V (1992) Phytochrome is involved in the light-regulation of vindoline biosynthesis in Catharanthus. Plant Physiol 100:1029-1032

Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title

Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generationof protein database search programs. Nucleic Acids Res 25: 3389-3402


Bastakis E, Hedtke B, Klermund C, Grimm B, Schwechheimer C (2018) LLM-domain B-GATA transcription factors play multifacetedroles in controlling greening in Arabidopsis. Plant Cell 30: 582-599


Behringer C, Schwechheimer C (2015) B-GATA transcription factors–insights into their structure, regulation, and role in plantdevelopment. Front Plant Sci 6: 90


Besseau S, Kellner F, Lanoue A, Thamm AM, Salim V, Schneider B, Geu-Flores F, Höfer R, Guirimand G, Guihur A, Oudin A, GlevarecG, Foureau E, Papon N, Clastre M, Giglioli-Guivarc'h N, St-Pierre B, Werck-Reichhart D, Burlat V, De Luca V, O'Connor SE,Courdavault V (2013) A pair of tabersonine 16-hydroxylases initiates the synthesis of vindoline in an organ-dependent manner inCatharanthus roseus. Plant Physiol 163: 1792-1803


Caputi L, Franke J, Farrow SC, Chung K, Payne RM, Nguyen T-D, Dang T-TT, Carqueijeiro IST, Koudounas K, de Bernonville TD,Ameyaw B, Jones DM, Vieira IJC, Courdavault V, O'Connor SE (2018) Missing enzymes in the biosynthesis of the anticancer drugvinblastine in Madagascar periwinkle. Science 360: 1235-1239


Cárdenas PD, Sonawane PD, Pollier J, Bossche RV, Dewangan V, Weithorn E, Tal L, Meir S, Rogachev I, Malitsky S, Giri AP, GoossensA, Burdman S, Aharoni A (2016) GAME9 regulates the biosynthesis of steroidal alkaloids and upstream isoprenoids in the plantmevalonate pathway. Nat Commun 7: 10654


Courdavault V, Papon N, Clastre M, Giglioli-Guivarc'h N, St-Pierre B, Burlat V (2014) A look inside an alkaloid multisite plant: theCatharanthus logistics. Curr Opin Plant Biol 19: 43-50


De Carolis E, Chan F, Balsevich J, De Luca V (1990) Isolation and characterization of a 2-oxoglutarate dependent dioxygenaseinvolved in the second-to-last step in vindoline biosynthesis. Plant Physiol 94: 1323-1329


De Luca V, Balsevich J, Tyler R, Eilert U, Panchuk B, Kurz W (1986) Biosynthesis of indole alkaloids: developmental regulation of thebiosynthetic pathway from tabersonine to vindoline in Catharanthus roseus. J Plant Physiol 125: 147-156


Franklin KA, Quail PH (2010) Phytochrome functions in Arabidopsis development. J Exp Bot 61: 11-24Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title

Geu-Flores F, Sherden NH, Courdavault V, Burlat V, Glenn WS, Wu C, Nims E, Cui Y, O'connor SE (2012) An alternative route to cyclicterpenes by reductive cyclization in iridoid biosynthesis. Nature 492: 138-142


Góngora-Castillo E, Childs KL, Fedewa G, Hamilton JP, Liscombe DK, Magallanes-Lundback M, Mandadi KK, Nims E, Runguphan W,Vaillancourt B, Varbanova-Herde M, DellaPenna D, McKnight TD, O'Connor S and Buell CR (2012) Development of transcriptomicresources for interrogating the biosynthesis of monoterpene indole alkaloids in medicinal plant species. PLoS ONE 7: e52506


Hudson D, Guevara DR, Hand AJ, Xu Z, Hao L, Chen X, Zhu T, Bi Y-M, Rothstein SJ (2013) Rice cytokinin GATA transcription Factor1regulates chloroplast development and plant architecture. Plant Physiol 162: 132-144


https://www.ncbi.nlm.nih.gov/pubmed?term=Aerts RJ%2C De Luca V %281992%29 Phytochrome is involved in the light%2Dregulation of vindoline biosynthesis in Catharanthus%2E Plant Physiol&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Aerts&hl=en&c2coff=1

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https://scholar.google.com/scholar?as_q=Phytochrome is involved in the light-regulation of vindoline biosynthesis in Catharanthus&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Aerts&as_ylo=1992&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Altschul SF%2C Madden TL%2C Sch�ffer AA%2C Zhang J%2C Zhang Z%2C Miller W%2C Lipman DJ %281997%29 Gapped BLAST and PSI%2DBLAST%3A a new generation of protein database search programs%2E Nucleic Acids Res&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Altschul&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=Gapped BLAST and PSI-BLAST: a new generation of protein database search programs&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=Gapped BLAST and PSI-BLAST: a new generation of protein database search programs&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Altschul&as_ylo=1997&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Bastakis E%2C Hedtke B%2C Klermund C%2C Grimm B%2C Schwechheimer C %282018%29 LLM%2Ddomain B%2DGATA transcription factors play multifaceted roles in controlling greening in Arabidopsis%2E Plant Cell&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Bastakis&hl=en&c2coff=1

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https://scholar.google.com/scholar?as_q=LLM-domain B-GATA transcription factors play multifaceted roles in controlling greening in Arabidopsis&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Bastakis&as_ylo=2018&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Behringer C%2C Schwechheimer C %282015%29 B%2DGATA transcription factors%26%23x2013%3Binsights into their structure%2C regulation%2C and role in plant development%2E Front Plant Sci&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Behringer&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=B-GATA transcription factors?insights into their structure, regulation, and role in plant development.&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=B-GATA transcription factors?insights into their structure, regulation, and role in plant development.&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Behringer&as_ylo=2015&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Besseau S%2C Kellner F%2C Lanoue A%2C Thamm AM%2C Salim V%2C Schneider B%2C Geu%2DFlores F%2C H�fer R%2C Guirimand G%2C Guihur A%2C Oudin A%2C Glevarec G%2C Foureau E%2C Papon N%2C Clastre M%2C Giglioli%2DGuivarc%27h N%2C St%2DPierre B%2C Werck%2DReichhart D%2C Burlat V%2C De Luca V%2C O%27Connor SE%2C Courdavault V %282013%29 A pair of tabersonine 16%2Dhydroxylases initiates the synthesis of vindoline in an organ%2Ddependent manner in Catharanthus roseus%2E Plant Physiol&dopt=abstract

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https://scholar.google.com/scholar?as_q=A pair of tabersonine 16-hydroxylases initiates the synthesis of vindoline in an organ-dependent manner in Catharanthus roseus&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Besseau&as_ylo=2013&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Caputi L%2C Franke J%2C Farrow SC%2C Chung K%2C Payne RM%2C Nguyen T%2DD%2C Dang T%2DTT%2C Carqueijeiro IST%2C Koudounas K%2C de Bernonville TD%2C Ameyaw B%2C Jones DM%2C Vieira IJC%2C Courdavault V%2C O%27Connor SE %282018%29 Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle%2E Science&dopt=abstract

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https://scholar.google.com/scholar?as_q=Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Caputi&as_ylo=2018&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=C�rdenas PD%2C Sonawane PD%2C Pollier J%2C Bossche RV%2C Dewangan V%2C Weithorn E%2C Tal L%2C Meir S%2C Rogachev I%2C Malitsky S%2C Giri AP%2C Goossens A%2C Burdman S%2C Aharoni A %282016%29 GAME9 regulates the biosynthesis of steroidal alkaloids and upstream isoprenoids in the plant mevalonate pathway%2E Nat Commun&dopt=abstract

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https://www.ncbi.nlm.nih.gov/pubmed?term=Courdavault V%2C Papon N%2C Clastre M%2C Giglioli%2DGuivarc%27h N%2C St%2DPierre B%2C Burlat V %282014%29 A look inside an alkaloid multisite plant%3A the Catharanthus logistics%2E Curr Opin Plant Biol&dopt=abstract

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https://scholar.google.com/scholar?as_q=A look inside an alkaloid multisite plant: the Catharanthus logistics&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Courdavault&as_ylo=2014&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=De Carolis E%2C Chan F%2C Balsevich J%2C De Luca V %281990%29 Isolation and characterization of a 2%2Doxoglutarate dependent dioxygenase involved in the second%2Dto%2Dlast step in vindoline biosynthesis%2E Plant Physiol&dopt=abstract

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https://www.ncbi.nlm.nih.gov/pubmed?term=De Luca V%2C Balsevich J%2C Tyler R%2C Eilert U%2C Panchuk B%2C Kurz W %281986%29 Biosynthesis of indole alkaloids%3A developmental regulation of the biosynthetic pathway from tabersonine to vindoline in Catharanthus roseus%2E J Plant Physiol&dopt=abstract

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https://scholar.google.com/scholar?as_q=Biosynthesis of indole alkaloids: developmental regulation of the biosynthetic pathway from tabersonine to vindoline in Catharanthus roseus&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=De&as_ylo=1986&as_allsubj=all&hl=en&c2coff=1

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https://www.ncbi.nlm.nih.gov/pubmed?term=Pattanaik S%2C Werkman JR%2C Kong Q%2C Yuan L %282010%29 Site%2Ddirected mutagenesis and saturation mutagenesis for the functional study of transcription factors involved in plant secondary metabolite biosynthesis%2E Methods Mol Biol&dopt=abstract

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https://www.ncbi.nlm.nih.gov/pubmed?term=Pauw B%2C Hilliou FA%2C Martin VS%2C Chatel G%2C de Wolf CJ%2C Champion A%2C Pr� M%2C van Duijn B%2C Kijne JW%2C van der Fits L%2C Memelink J %282004%29 Zinc finger proteins act as transcriptional repressors of alkaloid biosynthesis genes in Catharanthus roseus%2E J Biol Chem&dopt=abstract

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https://www.ncbi.nlm.nih.gov/pubmed?term=Payne RM%2C Xu D%2C Foureau E%2C Carqueijeiro MIST%2C Oudin A%2C de Bernonville TD%2C Novak V%2C Burow M%2C Olsen C%2DE%2C Jones DM%2C Tatsis EC%2C Pendle A%2C Ann Halkier B%2C Geu%2DFlores F%2C Courdavault V%2C Nour%2DEldin HH%2C O%27Connor SE %282017%29 An NPF transporter exports a central monoterpene indole alkaloid intermediate from the vacuole%2E Nat Plants&dopt=abstract

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https://www.ncbi.nlm.nih.gov/pubmed?term=Pham VN%2C Kathare PK%2C Huq E %282018%29 Phytochromes and phytochrome interacting factors%2E Plant Physiol&dopt=abstract

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https://www.ncbi.nlm.nih.gov/pubmed?term=Sib�ril Y%2C Benhamron S%2C Memelink J%2C Giglioli%2DGuivarc%27h N%2C Thiersault M%2C Boisson B%2C Doireau P%2C Gantet P %282001%29 Catharanthus roseus G%2Dbox binding factors 1 and 2 act as repressors of strictosidine synthase gene expression in cell cultures%2E Plant Mol Biol&dopt=abstract

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https://scholar.google.com/scholar?as_q=A Catharanthus roseus BPF-1 homologue interacts with an elicitor-responsive region of the secondary metabolite biosynthetic gene Str and is induced by elicitor via a JA-independent signal transduction pathway&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=van&as_ylo=2000&as_allsubj=all&hl=en&c2coff=1


production in the medicinal plant Catharanthus roseus. Plant J 88: 3-12Pubmed: Author and TitleGoogle Scholar: Author Only Title Only Author and Title

Van Moerkercke A, Steensma P, Schweizer F, Pollier J, Gariboldi I, Payne R, Bossche RV, Miettinen K, Espoz J, Purnama PC, Kellner F,Seppänen-Laakso T, O'Connor SE, Rischer H, Memelink J, Goossens A (2015) The bHLH transcription factor BIS1 controls the iridoidbranch of the monoterpenoid indole alkaloid pathway in Catharanthus roseus. Proc Natl Acad Sci USA 112: 8130-8135


Vazquez-Flota F, De Carolis E, Alarco AM, De Luca V (1997) Molecular cloning and characterization of desacetoxyvindoline-4-hydroxylase, a 2-oxoglutarate dependent-dioxygenase involved in the biosynthesis of vindoline in Catharanthus roseus (L.) G. Don.Plant Mol Biol 34: 935-948


Vazquez-Flota FA, De Luca V (1998) Developmental and light regulation of desacetoxyvindoline 4-hydroxylase in Catharanthus roseus(L.) G. Don. Evidence of a multilevel regulatory mechanism. Plant Physiol 117: 1351-1361


Vom Endt D, e Silva MS, Kijne JW, Pasquali G, Memelink J (2007) Identification of a bipartite jasmonate-responsive promoter elementin the Catharanthus roseus ORCA3 transcription factor gene that interacts specifically with AT-Hook DNA-binding proteins. PlantPhysiol 144: 1680-1689


Wang C, Meng L, Gao Y, Grierson D, Fu D (2018) Manipulation of light signal transduction factors as a means of modifying steroidalglycoalkaloids accumulation in tomato leaves. Front Plant Sci 9: 437


Weaver J, Goklany S, Rizvi N, Cram EJ, Lee-Parsons CW (2014) Optimizing the transient Fast Agro-mediated Seedling Transformation(FAST) method in Catharanthus roseus seedlings. Plant Cell Rep 33: 89-97


Xu Z, Casaretto JA, Bi YM, Rothstein SJ (2017) Genome-wide binding analysis of AtGNC and AtCGA1 demonstrates their cross‐regulation and common and specific functions. Plant Direct 1: e00016


Yadav V, Mallappa C, Gangappa SN, Bhatia S, Chattopadhyay S (2005) A basic helix-loop-helix transcription factor in Arabidopsis,MYC2, acts as a repressor of blue light–mediated photomorphogenic growth. Plant Cell 17: 1953-1966


Zhang H, Hedhili S, Montiel G, Zhang Y, Chatel G, Pré M, Gantet P, Memelink J (2011) The basic helix-loop-helix transcription factorCrMYC2 controls the jasmonate-responsive expression of the ORCA genes that regulate alkaloid biosynthesis in Catharanthusroseus. Plant J 67: 61-71


Zhang Y, Mayba O, Pfeiffer A, Shi H, Tepperman JM, Speed TP, Quail PH (2013) A quartet of PIF bHLH factors provides atranscriptionally centered signaling hub that regulates seedling morphogenesis through differential expression-patterning of sharedtarget genes in Arabidopsis. PLoS Genet 9: e1003244



https://www.ncbi.nlm.nih.gov/pubmed?term=Van Moerkercke A%2C Steensma P%2C Gariboldi I%2C Espoz J%2C Purnama PC%2C Schweizer F%2C Miettinen K%2C Vanden Bossche R%2C De Clercq R%2C Memelink J%2C Goossens A %282016%29 The basic helix%2Dloop%2Dhelix transcription factor BIS2 is essential for monoterpenoid indole alkaloid production in the medicinal plant Catharanthus roseus%2E Plant J&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Van&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=The basic helix-loop-helix transcription factor BIS2 is essential for monoterpenoid indole alkaloid production in the medicinal plant Catharanthus roseus&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=The basic helix-loop-helix transcription factor BIS2 is essential for monoterpenoid indole alkaloid production in the medicinal plant Catharanthus roseus&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Van&as_ylo=2016&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Van Moerkercke A%2C Steensma P%2C Schweizer F%2C Pollier J%2C Gariboldi I%2C Payne R%2C Bossche RV%2C Miettinen K%2C Espoz J%2C Purnama PC%2C Kellner F%2C Sepp�nen%2DLaakso T%2C O%27Connor SE%2C Rischer H%2C Memelink J%2C Goossens A %282015%29 The bHLH transcription factor BIS1 controls the iridoid branch of the monoterpenoid indole alkaloid pathway in Catharanthus roseus%2E Proc Natl Acad Sci USA&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Van&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=The bHLH transcription factor BIS1 controls the iridoid branch of the monoterpenoid indole alkaloid pathway in Catharanthus roseus&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=The bHLH transcription factor BIS1 controls the iridoid branch of the monoterpenoid indole alkaloid pathway in Catharanthus roseus&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Van&as_ylo=2015&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Vazquez%2DFlota F%2C De Carolis E%2C Alarco AM%2C De Luca V %281997%29 Molecular cloning and characterization of desacetoxyvindoline%2D4%2Dhydroxylase%2C a 2%2Doxoglutarate dependent%2Ddioxygenase involved in the biosynthesis of vindoline in Catharanthus roseus %28L%2E%29 G%2E Don%2E Plant Mol Biol&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Vazquez-Flota&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=Molecular cloning and characterization of desacetoxyvindoline-4-hydroxylase, a 2-oxoglutarate dependent-dioxygenase involved in the biosynthesis of vindoline in Catharanthus roseus (L&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=Molecular cloning and characterization of desacetoxyvindoline-4-hydroxylase, a 2-oxoglutarate dependent-dioxygenase involved in the biosynthesis of vindoline in Catharanthus roseus (L&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Vazquez-Flota&as_ylo=1997&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Vazquez%2DFlota FA%2C De Luca V %281998%29 Developmental and light regulation of desacetoxyvindoline 4%2Dhydroxylase in Catharanthus roseus %28L%2E%29 G%2E Don%2E Evidence of a multilevel regulatory mechanism%2E Plant Physiol&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Vazquez-Flota&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=Developmental and light regulation of desacetoxyvindoline 4-hydroxylase in Catharanthus roseus (L&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=Developmental and light regulation of desacetoxyvindoline 4-hydroxylase in Catharanthus roseus (L&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Vazquez-Flota&as_ylo=1998&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Vom Endt D%2C e Silva MS%2C Kijne JW%2C Pasquali G%2C Memelink J %282007%29 Identification of a bipartite jasmonate%2Dresponsive promoter element in the Catharanthus roseus ORCA3 transcription factor gene that interacts specifically with AT%2DHook DNA%2Dbinding proteins%2E Plant Physiol&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Vom&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=Identification of a bipartite jasmonate-responsive promoter element in the Catharanthus roseus ORCA3 transcription factor gene that interacts specifically with AT-Hook DNA-binding proteins&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=Identification of a bipartite jasmonate-responsive promoter element in the Catharanthus roseus ORCA3 transcription factor gene that interacts specifically with AT-Hook DNA-binding proteins&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Vom&as_ylo=2007&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Wang C%2C Meng L%2C Gao Y%2C Grierson D%2C Fu D %282018%29 Manipulation of light signal transduction factors as a means of modifying steroidal glycoalkaloids accumulation in tomato leaves%2E Front Plant Sci&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Wang&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=Manipulation of light signal transduction factors as a means of modifying steroidal glycoalkaloids accumulation in tomato leaves.&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=Manipulation of light signal transduction factors as a means of modifying steroidal glycoalkaloids accumulation in tomato leaves.&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Wang&as_ylo=2018&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Weaver J%2C Goklany S%2C Rizvi N%2C Cram EJ%2C Lee%2DParsons CW %282014%29 Optimizing the transient Fast Agro%2Dmediated Seedling Transformation %28FAST%29 method in Catharanthus roseus seedlings%2E Plant Cell Rep&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Weaver&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=Optimizing the transient Fast Agro-mediated Seedling Transformation (FAST) method in Catharanthus roseus seedlings&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=Optimizing the transient Fast Agro-mediated Seedling Transformation (FAST) method in Catharanthus roseus seedlings&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Weaver&as_ylo=2014&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Xu Z%2C Casaretto JA%2C Bi YM%2C Rothstein SJ %282017%29 Genome%2Dwide binding analysis of AtGNC and AtCGA1 demonstrates their cross�?�regulation and common and specific functions%2E Plant Direct 1%3A e&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Xu&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=Genome-wide binding analysis of AtGNC and AtCGA1 demonstrates their crossâ�?�regulation and common and specific functions.&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=Genome-wide binding analysis of AtGNC and AtCGA1 demonstrates their crossâ�?�regulation and common and specific functions.&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Xu&as_ylo=2017&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Yadav V%2C Mallappa C%2C Gangappa SN%2C Bhatia S%2C Chattopadhyay S %282005%29 A basic helix%2Dloop%2Dhelix transcription factor in Arabidopsis%2C MYC2%2C acts as a repressor of blue light%26%23x2013%3Bmediated photomorphogenic growth%2E Plant Cell&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Yadav&hl=en&c2coff=1


https://scholar.google.com/scholar?as_q=&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Yadav&as_ylo=2005&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Zhang H%2C Hedhili S%2C Montiel G%2C Zhang Y%2C Chatel G%2C Pr� M%2C Gantet P%2C Memelink J %282011%29 The basic helix%2Dloop%2Dhelix transcription factor CrMYC2 controls the jasmonate%2Dresponsive expression of the ORCA genes that regulate alkaloid biosynthesis in Catharanthus roseus%2E Plant J&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Zhang&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=The basic helix-loop-helix transcription factor CrMYC2 controls the jasmonate-responsive expression of the ORCA genes that regulate alkaloid biosynthesis in Catharanthus roseus&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=The basic helix-loop-helix transcription factor CrMYC2 controls the jasmonate-responsive expression of the ORCA genes that regulate alkaloid biosynthesis in Catharanthus roseus&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Zhang&as_ylo=2011&as_allsubj=all&hl=en&c2coff=1

https://www.ncbi.nlm.nih.gov/pubmed?term=Zhang Y%2C Mayba O%2C Pfeiffer A%2C Shi H%2C Tepperman JM%2C Speed TP%2C Quail PH %282013%29 A quartet of PIF bHLH factors provides a transcriptionally centered signaling hub that regulates seedling morphogenesis through differential expression%2Dpatterning of shared target genes in Arabidopsis%2E PLoS Genet 9%3A e&dopt=abstract

https://scholar.google.com/scholar?as_q=&num=10&as_occt=any&as_sauthors=Zhang&hl=en&c2coff=1

https://scholar.google.com/scholar?as_q=A quartet of PIF bHLH factors provides a transcriptionally centered signaling hub that regulates seedling morphogenesis through differential expression-patterning of shared target genes in Arabidopsis.&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_publication=&as_yhi=&as_allsubj=all&hl=en&lr=&c2coff=1

https://scholar.google.com/scholar?as_q=A quartet of PIF bHLH factors provides a transcriptionally centered signaling hub that regulates seedling morphogenesis through differential expression-patterning of shared target genes in Arabidopsis.&num=10&btnG=Search+Scholar&as_occt=any&as_sauthors=Zhang&as_ylo=2013&as_allsubj=all&hl=en&c2coff=1


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GATA and PIF transcription factors regulate light-induced ...€¦ · significantly induce the indole and iridoid pa. thway genes, resulting in increased accumulation of . 92. strictosidine,