Genome-Wide DNA Methylation Profiling Identifies Differential Methylation in Uninvolved Psoriatic Epidermis Deepti Verma, Anna-Karin Ekman, Cecilia Bivik Eding and Charlotta Enerbäck

The self-archived postprint version of this journal article is available at Linköping University Institutional Repository (DiVA): http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-147791 N.B.: When citing this work, cite the original publication. Verma, D., Ekman, A., Bivik Eding, C., Enerbäck, C., (2018), Genome-Wide DNA Methylation Profiling Identifies Differential Methylation in Uninvolved Psoriatic Epidermis, Journal of Investigative Dermatology, 138(5), 1088-1093. https://doi.org/10.1016/j.jid.2017.11.036

Original publication available at: https://doi.org/10.1016/j.jid.2017.11.036

Copyright: Elsevier http://www.elsevier.com/

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Genome-Wide DNA Methylation Profiling Identifies Differential Methylation in Uninvolved Psoriatic Epidermis

Deepti Verma*a, Anna-Karin Ekman*a, Cecilia Bivik Edinga and Charlotta Enerbäcka

*Authors contributed equally

aIngrid Asp Psoriasis Research Center, Department of Clinical and Experimental Medicine,

Division of Dermatology, Linköping University, Linköping, Sweden

Corresponding author:

Charlotta Enerbäck

Ingrid Asp Psoriasis Research Center, Department of Clinical and Experimental Medicine, Linköping University

SE-581 85 Linköping, Sweden

Phone: +46 10 103 7429

E-mail: charlotta.enerback@liu.se

Short title

Differential methylation in psoriasis

Abbreviations

CGI, CpG island; DMS, differentially methylated site; RRBS, reduced representation bisulphite sequencing

Keywords (max 6)

psoriasis, epidermis, methylation, Wnt, susceptibility, expression

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ABSTRACT

Psoriasis is a chronic inflammatory skin disease with both local and systemic components.

Genome-wide approaches have identified more than 60 psoriasis-susceptibility loci, but genes

are estimated to explain only one third of the heritability in psoriasis, suggesting additional, yet

unidentified, sources of heritability. Epigenetic modifications have been linked to psoriasis and

altered DNA methylation patterns in psoriatic versus healthy skin have been reported in whole-

skin biopsies. In this study, focusing on epigenetic modifications in the psoriatic uninvolved

skin, we compared the lesional and non-lesional epidermis from psoriasis patients with

epidermis from healthy controls. We performed an exhaustive genome-wide DNA methylation

profiling using reduced representation bisulfite sequencing, which interrogates the methylation

status of ~3-4 million CpG sites. More than two thousand strongly differentially methylated

sites (DMS) were identified and a striking overrepresentation of the Wnt and cadherin

pathways among the DMS was found. In particular, we observe a strong differential

methylation in several psoriasis candidate genes. A substantial number of DMS present in the

uninvolved vs healthy epidermis suggests the presence of a pre psoriatic state in the clinically

healthy skin type. Our exploratory study represents a starting point for identifying biomarkers

for psoriasis-prone skin before disease onset.

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INTRODUCTION

The genetic component in psoriasis pathogenesis is well recognized, and genome-wide

association studies (GWAS) have identified more than 60 psoriasis-susceptibility loci

(Ellinghaus et al., 2010, Nair et al., 2009, Tang et al., 2014, Tsoi et al., 2012). However, it is

estimated that the identified genes explain only 28% of the heritability of psoriasis, suggesting

additional, yet unidentified, sources of heritability (Tsoi et al., 2015).

The incomplete concordance in disease status between monozygotic twins suggests a role for

environmental factors in psoriasis pathogenesis (Das et al., 2009). Environmental triggers, such

as infections, stress, injuries, smoking, alcohol and lithium medication, can induce an auto-

inflammatory response mediated by DNA methylation in genetically predisposed individuals

(Baker et al., 1997, Tsankov et al., 2000). Since parental exposure to environmental triggers

has been shown to affect the transgenerational transmission of altered DNA methylation

(Trerotola et al., 2015), epigenetics may contribute to the missing heritability in psoriasis.

The aim of this study was to investigate the epigenetic regulation underlying psoriasis

susceptibility. Previous studies using Illumina’s 27-450K resolution have shown aberrant DNA

methylation in psoriatic lesional (PP) when compared with non-lesional (PN) or healthy skin

(NN) (Gu et al., 2015, Roberson et al., 2012, Zhou et al., 2016). Using whole-biopsy samples,

Roberson et al. detected intermediate methylation of uninvolved skin and found 15

differentially methylated sites between PN/NN. However, an in-depth comparison of

methylation differences between PN and NN skin is lacking. We performed an extensive

investigation of the methylome in PP, PN and NN epidermis covering three-four million CpG

residues. We report more than 2,000 strongly differentially methylated sites (DMS), thereby

clearly distinguishing the skin phenotypes. Substantial methylation differences between non-

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lesional and healthy epidermis, involving the Wnt and cadherin pathways, is to our knowledge

previously unreported.

RESULTS

Global DNA methylation profiling of PP, PN and NN epidermis

Using reduced representation bisulphite sequencing (RRBS) to map the global CpG

methylation state, we obtained ~21-52 million total reads in the samples, with a mean value of

35,899,496 per sample. The mapping efficiency ranged from 48-59%, with an average of

19,060,737 sites successfully aligning back to the human genome (UCSC hg19) and the read

depth ranged from six to nine fold. The technical validation of RRBS data using

pyrosequencing showed highly consistent results for all the tested sites (data not shown). Using

flow cytometry, the CD45+ leukocyte population was found to contribute less than 2.4% of the

total cells (data not shown).

The number of covered CpG sites and DMS are shown in Table 1. The genomic distribution

of these sites are represented in Supplementary Figures 1a-d.

The top 2,000 DMS showing greater than 33% differential methylation in the pairwise

comparisons, demonstrated several overrepresented pathways relevant for psoriasis

(Supplementary Table 1). Using a significant threshold of a Bonferroni-adjusted p-value of

0.05, we found common enrichments of pathways like cadherin (PN/NN PBonferroni = 2.8x10-9,

PP/PN PBonferroni = 8.5x10-21, PP/NN PBonferroni= 6.2x 10-9) and Wnt (PN/NN PBonferroni = 2.8x10-7,

PP/PN PBonferroni = 2x10-20, PP/NN P Bonferroni = 3.5x10-10). The pathways exclusively detected in

the lesional skin when compared with the non-lesional or healthy skin were heterotrimeric G-

protein signaling (PP/PN PBonferroni =1.19x10-3, PP/NN PBonferroni = 1.13x10-2) and inflammation

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mediated through cytokines and chemokines (PP/PN PBonferroni = 3.6 x10-2, PP/NN PBonferroni =

2.9 x10-2), which might reflect accelerated cell growth and sustained inflammation.

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The CpG methylation pattern in the psoriasis-susceptible and the lesional epidermis

compared with the normal epidermis

The PN/NN comparison revealed a substantial number of DMS (Figure 1a). The DMS

overlapping between the PN/NN and PP/NN comparisons likely represent a methylation

pattern that is intrinsic to the psoriatic skin, rather than resulting from the inflammatory process

(Figure 1b, Supplemental data S1). The overlapping genes show an overrepresentation of the

Wnt and cadherin pathways (P Bonferroni = 3.1x10-6 and 4x 10-8, respectively). Using the recent

Reactome resource in PANTHER (Mi et al., 2017) we found that these genes were enriched in

non-canonical Wnt signaling (PBonferroni = 2 x10-2). The Wnt-pathway regulating genes

including Wnt7B, NFATc1, CELSR2 and FZD7 demonstrated >33% differential methylation at

multiple sites. FZD7, the Frizzled receptor for Wnt proteins, is differentially expressed in

psoriasis (Gudjonsson et al., 2010). IL23R, which has a strong pathogenic association with

psoriasis (Harden et al., 2015), was hypermethylated in both the PN/NN and PP/NN.

The CpG methylation pattern in the psoriasis-susceptible and the normal epidermis

compared with the psoriatic lesion

The overlap between the PN and NN epidermis (Figure 1b) when compared with PP likely

represents a methylation pattern induced by the inflammatory or disease-related state. The

genes overlapping between the PP/NN and PP/PN (Supplemental Data S1) displayed

prominent overrepresentations of the cadherin (PBonferroni = 3.2x10-10) and Wnt pathways

(PBonferroni = 1.9x10-7). In addition, overrepresentations of the heterotrimeric G-protein

signaling Gq alpha- and Go alpha- mediated pathway (PBonferroni = 1.4x10-2) and the integrin

pathway (PBonferroni = 7.8 x10-4) were found. The overlapping cadherin and Wnt genes were

enriched for non-canonical Wnt signaling (PBonferroni = 5x10-10) and Ca2+ pathways (PBonferroni

= 3x10-9). Calcium is a key second messenger in the non-canonical Wnt signaling (Kohn and

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Moon, 2005). Furthermore, SFRP4, a negative regulator of Wnt signaling, Wnt5A and its

receptor FZD2 were found to be differentially methylated.

The > 33% hypermethylated genes included DUSP1 and EXPH5, which presented at several

sites in the PP/PN and PP/NN. The hypermethylation of DUSP1, a negative regulator of p38

mitogen-activated protein kinase activity, was in accordance with its reported downregulation

in psoriasis (Kjellerup et al., 2013). EXPH5 is a GTPase effector protein and is implicated in

inherited skin fragility disease (McGrath et al., 2012). A known susceptibility locus for

psoriasis, GJB2, was found to be > 33% hypomethylated at several sites, which is in accordance

with its reported upregulation in psoriasis (Sun et al., 2010).

To exclude the universally expressed genes, we made use of the Body Index of human Gene

Expression (BIGE) database (Gerber et al., 2013), which includes 687 skin-associated genes

(SAGs). Upon intersecting our methylation data with the SAGs, we found 340 common

matches for the PP/NN and 223 common matches for the PN/NN comparison (Supplemental

data S2 & S3). GO analysis revealed the considerable enrichment of terms related to

desmosome organization, keratinocyte proliferation and skin-barrier function (Figure 1c),

suggesting a role for methylation in the regulation of a substantial number of skin-specific

genes.

Methylation levels distinguish involved, uninvolved and normal epidermis

To determine whether the PN and NN can be distinguished based on the differences in

methylation pattern, we selected the 100 most DMS between the PP and NN comparisons. We

performed an unsupervised hierarchical clustering, including the PN samples, which revealed

a distinct clustering between the PP, NN and PP (Figure 2a). The PN samples, albeit in a distinct

cluster, displayed a methylation pattern that more closely resembled the NN than the PP

epidermis.

Altered methylation at the psoriasis risk-associated loci

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Two recent meta-analysis identified 59 replicated psoriasis risk-associated genes (Tsoi et al.,

2015, Tsoi et al., 2017. The genes are listed in the Supplemental data S4). We investigated the

level of DNA methylation for all the CpG sites in these psoriasis risk-associated genes,

including their promoters. Using a permutation test, we found 38 sites with >33% DMS among

the psoriasis candidate genes, which was greater than expected by chance (P < 0.01). These

sites mainly annotated to the candidate genes TRAF3IP2, ZMIZ1 and CARD14. The number of

such DMS in the top 15 cis-acting eQTLs in psoriatic lesional skin (Ding et al., 2010) was not

found to be greater than expected by chance (P = 0.92).

Transcriptomic profiling of epidermis

We found a distinct differential gene expression in the PP/PN (496 differentially expressed

genes) and PP/NN comparisons (587 differentially expressed genes). The hallmark genes

(IL36G, KYNU, RHCG, ATP12A, HPSE, CCL20, SERPINB13, SOX7 and C20orF24),

universally shown to be upregulated in psoriatic full-thickness skin (Swindell et al., 2014),

displayed an increased expression in our epidermal samples from the PP/NN and PP/PN

comparisons.

An unsupervised hierarchical clustering of the top differentially expressed sites resulted in the

absence of clustering between the PN and the NN samples, indicating that the expression

differences between them are subtle (Figure 2b).

Association of mRNA expression with methylation levels in the epidermis

Using a differential methylation cut-off of 33%, we found 44 shared genes in the PP/NN and

41 shared genes in the PP/PN. The genes DUSP1 and GATA3, both previously shown to be

downregulated in psoriasis (Kjellerup et al., 2013, Racz et al., 2011), demonstrated several >

33% DMS, along with a corresponding transcriptional downregulation in the PP/NN

comparison. Additional genes with key skin-regulatory functions, where hypermethylation

correlated with a downregulated expression, included EXPH5, AHNAK, PTPN14, NR1D1 and

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PTPN21 (Gerber et al., 2013). Strongly hypomethylated genes with an upregulated

transcription in the PP/NN comparison included FOXE1, GJB2, RAB31, WWOX, ATP1B1,

SLC7A5 and SOX7, all of which have been implicated in psoriasis (Suarez-Farinas et al., 2012).

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DISCUSSION

We report a comprehensive genome-wide analysis using epidermal samples to study global

DNA methylation and RNA expression patterns in psoriasis. We utilized the next-generation

sequencing-based technique RRBS to investigate DNA methylation in the epidermis derived

from lesional and non-lesional psoriasis and from normal skin. The epidermis was removed

using ammonium thiocyanate, a method that does not affect gene expression (Clemmensen et

al., 2009). In order to minimize the confounding effects of cell heterogeneity, we specifically

analyzed the epidermis rather than the full-thickness skin.

A few studies using the Illumina’s 27-450K resolution in full-thickness skin, have reported a

difference in methylation between the PP skin and the PN or NN skin (Roberson et al., 2012,

Zhou et al., 2016). Using almost 10 times the number of probes, we now provide additional,

comprehensive data, and validate the previous findings. Using the Illumina 27K, Roberson et

al (Roberson et al., 2012) identified 1,108 differentially methylated genes, of which 443 were

found in our pairwise PP/NN comparison. We also identified six (MANI1C1, SPIRE2, AHDC1,

DLGAP4, ECE1 and CYP2S1) of the nine differentially methylated loci recently described by

Zhou et al (Zhou et al., 2016). Several DMS mapped to the GWAS psoriasis-risk genes and

altered methylation at multiple sites were observed for TRAF3IP2, ZMIZ1 and CARD14.

Substantial differential methylation was evident in the comparison of PN and NN. Intriguingly,

these DMS included several sites (328 genes) identified by Roberson et al., as well as five of

the nine sites described by Zhou et al. in the PP/NN comparisons, showing that the methylation

differences not only delineate the lesional and healthy skin but also the clinically normal,

uninvolved skin from the healthy skin. When comparing DMS present in both PP and PN

compared with NN, a strong overrepresentation of differentially methylated Wnt and cadherin

pathway genes was found, which were significantly enriched for the non-canonical Wnt/Ca2+

signaling. Wnt signaling plays critical roles in embryogenesis and tissue homeostasis. NFATc1,

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a WNT5A downstream gene implicated in non-canonical Wnt signaling, demonstrated DMS at

multiple sites. Interestingly, NFATc1 was recently shown to be important for imiquimod-

induced psoriasiform dermatitis by suppressing IL-10 in B cells (Alrefai et al., 2016).

When comparing the PP skin with the PN (or NN) skin, we attempted to filter out the changes

in methylation that are a consequence of the inflammatory reaction in lesional skin to

distinguish them from the changes that underlie disease susceptibility. An overrepresentation

of DMS associated with Wnt signaling was found and included SFRP4, a negative regulator of

Wnt signaling, which was recently shown to be downregulated in psoriasis through an

epigenetic mechanism (Bai et al., 2015). SFRP4 directly inhibited keratinocyte proliferation

triggered by proinflammatory cytokines in vitro (Bai et al., 2015). Moreover, we found

differential methylations of Wnt5A, as well as its receptor, FZD2. Wnt5a is an important pro-

inflammatory factor that has been implicated in several inflammatory diseases, such as

rheumatoid arthritis, atherosclerosis and psoriasis (Pashirzad et al., 2016). The expression of

Wnt5A is increased in psoriatic epidermis, together with its receptors, FZD2 and FZD5

(Gudjonsson et al., 2010, Reischl et al., 2007, Romanowska et al., 2009). Interestingly, Wnt5A

is one of the very few genes that retain increased expression in resolving psoriatic lesions

(Suarez-Farinas et al., 2011).

As previously reported (Roberson et al., 2012, Zhang et al., 2013, Zhou et al., 2016), we found

that relatively few, albeit functionally relevant, subsets of genes overlapped between

methylation and expression. Unlike the clear distinction in the methylation pattern between the

PN and NN samples, the differences in gene expression between these groups were subtle. This

suggests that DNA methylation does not directly translate into altered expression but may poise

the associated genes for expression in response to future triggers.

The differences between PN and NN might be influenced by the underlying systemic/local

inflammation or genetic factors. The increased inflammatory activity in PN skin was suggested

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by Johnson-Huang et al, who demonstrated infiltrating CD3+ T-cells, and inflammatory DCs

in PN skin in patients with psoriasis (Johnson-Huang et al., 2012). In favor of an intrinsic

abnormality in PN skin is our recent finding of an apoptosis-resistant phenotype in cultured

uninvolved psoriatic skin. Interestingly, this effect persisted after several passages of culture

(Bivik Eding and Enerback, 2017). Moreover, uninvolved skin demonstrated abnormal barrier

function and differential in vitro keratinocyte spreading (Chen et al., 2001, Ye et al., 2014).

In conclusion, we demonstrate substantial methylation differences between uninvolved

psoriatic skin and healthy skin, suggesting that the uninvolved skin might represent a pre-

psoriatic state. Further studies are required to identify the biological mechanisms underlying

the altered methylation patterns in PN vs NN skin.

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MATERIAL AND METHODS

The detailed protocols and statistical analysis are described in Supplemental methods.

Study population and samples

Written informed consent was obtained from the patients and control subjects, and the ethical

principles of the Declaration of Helsinki were followed. The study was approved by the

Regional ethics committee in Linkoping. Skin punch biopsies (4 mm) were obtained from

psoriasis patients and controls. The psoriasis diagnosis had been confirmed by a dermatologist.

The participating patients were not receiving any systemic treatment, and the lesions from

which the skin biopsies were obtained were untreated. The PP biopsies were taken from the

lower back in an active psoriasis lesion and PN skin was obtained from a non-lesional area on

the lower back of the same patient at least 10 cm from the active, lesional skin. A total of 12

biopsies, six from psoriasis patients (including three pairwise PP and PN) and six NN biopsies,

were obtained. All participants were males, to avoid confounding gender-specific methylation

patterns (Liu et al., 2010). The epidermis was detached by soaking the biopsy in 3.8% sterile

ammonium thiocyanate in PBS for 30 minutes, as previously described (Clemmensen et al.,

2009). DNA was immediately isolated using the Blood and Tissue DNA extraction kit

(QIAGEN, Hilden, Germany).

Methylation analysis

The DNA samples were processed for genome-wide DNA methylation sequencing analysis by

Zymo Research (Irvine, CA) (Supplementary methods). The CpG sites having a minimum

read-depth of five and a methylation difference cut-off ±10%, were annotated into promoter,

exon, intron or CpG island. The gene boundary was defined by RefSeq annotations for the

human genome (UCSC hg19) and the promoter was defined as +/- 1 kb from the transcription

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start site of the gene. The methylation level of each sampled cytosine was estimated as the

number of methylated cytosines divided by the total number of cytosines. Pairwise

comparisons were done for PP/NN, PP/PN and PN/NN samples. The methylation difference

for each site was calculated by subtracting the median methylation value of the sample of

interest from the reference sample. For increased stringency, we based our analyses on the top

2,000 DMS with a differential methylation cut off of 33%.

Gene ontology (GO) annotation

The PANTHER (http://www.PANTHERdb.org/) database was used for the gene ontology and

pathway overrepresentation analysis. Official gene symbols were used as input to calculate the

statistical overrepresentation of biological process GO terms.

Gene expression profiling

Gene expression was determined using Affymetrix Beadchip 2.0 (Affymetrix, Santa Clara,

CA), following the manufacturer’s instructions. The differential expression of genes was

determined using the GeneSpring GX software (Agilent technologies, Santa Clara, CA), with

a cut-off of ±1.5 f.c.

Statistics

The statistical significance of the methylation difference was determined by the Student’s t‐

test or the Fisher’s Exact Test. Statistical overrepresentation of PANTHER pathways was

determined using a Bonferroni correction. The differential methylation of CpG sites in psoriasis

candidate genes and eQTL loci were investigated using a permutation test.

Data Access

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The DNA methylation data have been deposited in the NCBI Gene Expression Omnibus

database under accession number GSE 103038.

Conflict of interest

The authors declare no conflict of interest

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TABLES

Table 1. Distribution of differentially methylated sites in the pairwise comparisons

DMS: Differentially methylated sites

FIGURE LEGENDS

Figure 1. Differentially methylated sites in the pairwise comparisons. (a) Volcano plot showing the

differentially methylated sites in the PN/NN comparison. Sites showing > ± 10% differential

methylation are shown. Blue dots represent the strongly hyper/hypo-methylated sites > ± 33% (b) Venn

diagrams showing the number of overlapping hyper and hypo methylated annotated sites in the pairwise

comparisons PP/NN, PP/PN and PN/NN (c) Displays gene ontology (GO) enrichments of the top 10

GO terms obtained upon intersecting the differentially methylated genes in PN/NN and PP/NN with the

Skin-Associated Genes (SAG) database. PN, Uninvolved; NN, Healthy; PP, Involved

Figure 2. Differential methylation and gene expression profiles. (a) Heat map of the PP (N =3), NN

(N=6) and PN (N=3) samples. Methylation ratio values of the top 100 DMS that distinguish PP from

NN epidermis were used. Unsupervised hierarchical clustering, upon including the same sites from PN,

are shown. Red color indicates a hypomethylation and yellow color indicates a hypermethylation. (b)

Heat map of the normalized expression values of the top 50 differentially expressed genes that

distinguish PP from NN epidermis. Unsupervised hierarchical clustering, upon including the same sites

from PN, are shown. The yellow values indicate a relative increase, while the red values indicate a

relative decrease in expression. PN, Uninvolved; NN, Healthy; PP, Involved

PP vs NN PP vs PN PN vs NN Total sites 2,072,217 3,058,077 2,007,044 DMS 83,587 58,627 35,056 Hypomethylated 44,528 29,558 25,546

Strongly hypomethylated 5,364 2,762 1,644 Hypermethylated 39,059 29,069 9,511 Strongly hypermethylated 8,504 4,556 669

Supplemental methods

Identification of epidermal cell populations by flow cytometry

The phenotyping of epidermal cells was performed using the Gallios flow cytometer. FITC-

conjugated monoclonal mouse anti-human antibody against CD45 (clone HI30, BD

Bioscience, San Jose, CA) was used and the percentage of CD45+ cells was determined using

Kaluza software (Beckman Coulter, CA).

Methyl-MiniSeq™ library construction

Libraries were prepared from 200-500 ng of genomic DNA, digested with 60 units of TaqαI

and 30 units of MspI (NEB) sequentially and then extracted with a Zymo Research (ZR) DNA

Clean & Concentrator™-5 kit. Fragments were ligated to pre-annealed adapters containing 5’-

methyl-cytosine instead of cytosine, according to Illumina’s specified guidelines

(www.illumina.com). Adaptor-ligated fragments 150-250 bp and 250-350 bp in size were

recovered from a 2.5% NuSieve 1:1 agarose gel (Zymoclean™ Gel DNA Recovery Kit, ZR).

The fragments were then bisulfite treated using the EZ DNA Methylation-Lightning™ Kit

(ZR). Preparative-scale PCR was performed and the resulting products were purified (DNA

Clean & Concentrator™ – ZR) for sequencing on an Illumina HiSeq.

Methyl-MiniSeq™ Sequence alignments and data analysis

Sequence reads from bisulfite-treated EpiQuest libraries were identified using standard

Illumina base-calling software and then analyzed using a Zymo Research proprietary analysis

pipeline, which uses Bismark (http://www.bioinformatics.babraham.ac.uk/projects/bismark/)

to perform the alignment. Index files were constructed using the bismark_genome_preparation

command and the entire reference genome. The --non_directional parameter was applied while

running Bismark. All other parameters were set to default. Filled-in nucleotides were trimmed

off while performing methylation calling.

Bisulphite pyrosequencing

Five statistically significant CpGs showing strong differential methylation were selected for

the technical validation of RRBS in the PP, PN and NN samples. Bisulphite conversion was

performed using the manufacturer’s protocol (EZ DNA methylation kit, Zymo Research) and

pyrosequencing was performed on the Pyromark™ Q24 system (QIAGEN).

Permutation test

The statistical significance of CpG sites in the psoriasis candidate genes and eQTL loci was

determined using a threshold of 33% differential methylation. The number of differentially

methylated CpG sites were counted in the psoriasis candidate genes or in the eQTL loci and

compared to the mean number of sites ± standard deviation in the randomly permutated

samples. P < 0.05 was considered to be significant.

Supplementary figures and tables

Supplementary Figure S1. Genomic distribution of the CpG sites. (A) Illustrates the distribution

of all the covered CpG sites in the pairwise PN/NN, PP/PN and PP/NN comparisons, (B-D) Illustrates

the distribution of the hypermethylated (black bars)and hypomethylated (grey bars) CpG sites in the

pairwise comparisons.

Supplementary Table S1. Overrepresentation of PANTHER pathways in the pairwise

comparisons

Supplementary table S1.

Top 2000 hypomethylated genes in PN vs NN

PANTHER Pathways

No. of

genes Fold Enrichment Bonferroni corrected P value

Cadherin signaling pathway (P00012) 29 4.70 2.85E-09

Endothelin signaling pathway (P00019) 12 3.57 3.03E-02

PDGF signaling pathway (P00047) 19 3.27 1.66E-03

Wnt signaling pathway (P00057) 38 3.13 2.48E-07

Top 2000 hypermethylated genes in PN vs NN

PANTHER Pathways

No. of

genes Fold Enrichment Bonferroni corrected P value

Alpha adrenergic receptor signaling pathway (P00002) 7 8.14 5.03E-03

Cadherin signaling pathway (P00012) 28 5.15 7.46E-10

Wnt signaling pathway (P00057) 39 3.65 1.86E-09

Gonadotropin-releasing hormone receptor pathway (P06664) 20 2.48 4.11E-02

Top 2000 hypomethylated genes in PP vs NN

PANTHER Pathways

No. of

genes Fold Enrichment Bonferroni corrected P value

Cadherin signaling pathway (P00012) 26 5.06 6.27E-09

B cell activation (P00010) 11 4.70 5.19E-03

Wnt signaling pathway (P00057) 39 3.86 3.52E-10 Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated

pathway (P00027) 14 3.50 1.13E-02

Integrin signalling pathway (P00034) 17 2.72 4.00E-02

Inflammation mediated by chemokine and cytokine signaling pathway (P00031) 21 2.47 2.92E-02

No pathways overrepresented for top 2000 hypermethylated genes in PP vs

NN

Top 2000 hypomethylated genes in PP vs PN

PANTHER Pathways

No. of

genes Fold Enrichment Bonferroni corrected P value

Cadherin signaling pathway (P00012) 43 7.18 8.57E-21

Histamine H1 receptor mediated signaling pathway (P04385) 9 5.40 9.52E-03

Wnt signaling pathway (P00057) 58 4.92 2.27E-20

Oxytocin receptor mediated signaling pathway (P04391) 10 4.55 1.53E-02

5HT2 type receptor mediated signaling pathway (P04374) 10 3.94 4.80E-02

Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated

pathway (P00027) 17 3.65 1.19E-03 Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated

pathway (P00026) 18 2.90 1.28E-02

Inflammation mediated by chemokine and cytokine signaling pathway (P00031) 23 2.32 3.63E-02

Top 2000 hypermethylated genes in PP vs PN

PANTHER Pathways

No. of

genes Fold Enrichment Bonferroni corrected P value

Angiogenesis (P00005) 18 2.74 2.55E-02

Gonadotropin-releasing hormone receptor pathway (P06664) 21 2.39 4.65E-02

Supplemental data S1.

PN vs NN and PP vs PN and

PP vs NN overlapping genes PP vs NN overlapping genes COQ7 IFITM2 PCSK9 ZBTB47 CASC4 SLC30A2

SLC25A30 PIGL TNFRSF18 RARRES1 CIB2 HPCA

GNL2 GRM4 GUK1 FGFR3 SEMA4B IFI44

IL23R TTC27 CTNNBIP1 RAPGEF2 DNM1P46 SLC6A17

MRAS B4GALNT1 TSPAN1 FBXW7 SNORD115-17 NTRK1

PROSER2 CCDC144NL MIR4252 LOC339975 WDR76 ATP1A2

DNMT3B ANKRD12 KIF1B PLA2G12A CYP1A2 RGS5

FAM57A RBM24 ZBTB48 DUX4L6 MIR147B KIAA1614

LINC00320 ITGB2-AS1 FGR TBC1D14 COX5A LOC440704

HPGDS LRP12 SCMH1 BMPR1B SCAMP5 MDM4

COL18A1 LOC283922 NBPF1 PITX2 PPCDC PADI3

SYBU PGAM5 ARHGAP29 PPP2R2C FLJ42289 ZNF683

FAAH2 CENPH VASH2 PKD2 ANPEP CD1C

TNFRSF18 OTOS C1orf86 ERVMER34-1 TARSL2 TCEB3

AQP11 CNTRL C1orf86 FAM160A1 MIR5189 KHDRBS1

CAMKV FAM173B THAP3 SPOCK3 FBXL16 MANEAL

PRR22 CDR2L LOC100506795 OTOP1 DEXI RAVER2

LCT USP24 RNF223

HHIP-AS1

HHIP ALDOA SLC25A44

PTK7 HHIPL2 MAPKAPK2 PPEF2 ANKRD26P1 HMCN1 MIR548F1

ROBO4 SLC3A2 GJB3 SETD7

SSTR5 SSTR5-

AS1 KCNT2

CAPN14 UCP2 LRP8 GPM6A LOC100128881 GPR25

INPP5F SUOX ADAM15 IDUA HAS3 AVPR1B

TSPAN32 STARD13 ADCY10 FAM114A1 MIR574 MTHFSD MFN2

ELMO3 ADPRHL1 CDK11B GABRA2 IQCK MDS2

LOC93622 EAPP ARHGEF2 DCHS2 IL4R CEP85

GTF2B PSEN1

DISC1

TSNAX-DISC1 CCDC149 MT1X TMEM61

COG6 IVD LGR6 MAB21L2 MYLK3 KIAA1324

TMC3 BBS2 TAF5L FHDC1 CMIP VTCN1

C19orf21 PHLPP2 LOC284632 SOWAHB KCNG4 SFT2D2

PHGDH HS3ST3B1 ARNT EMCN ZDHHC7 FMO1

BRSK2 ATXN7L3 FCRL3 HOPX CHP2 CRB1

MYOM1 MARCH10 TAS1R1 CCDC158 LINC00273 CAPN2

ABCA1 SOCS3 EFHD2 TSPAN5 PRSS8 LOC149134

HSPB7 TUBB4A PTP4A2 ANK2 MIR5587 SLFNL1

RSPO1 SYDE1 PIK3C2B SH3D19 B3GNT9 EPS15

POLR1D PQLC3 PLEKHG5 NAT8L CACNG3 ZCCHC11

RGS19 CHST10 MIR4695 GPR78 NTHL1 GJA5

MYL5 EPB41L5 QSOX1 GPR125 RPS15A LINC00869 LINC00623

AGPAT4-IT1 ABCB6 SUCLG1 LOC100506035 UMOD STX6

FAM63A FAM83C LGALSL C4orf22 NLRC5 GPR157

DEDD2 NKAIN4 FLJ16779 RNPEPL1 ZNF876P PLLP MASP2

MIR5684 CMSS1 FILIP1L DPP4 IDUA SLC9A5 FBXO42

TSPYL4 COPG1 SPRED2 NKX3-2 FAM195A STMN1

SLTM ZIC4 GPC1 PP14571 LCORL METRN EYA3

MIR196A1 LEPREL1 ATL2 CXCL13 PDPK1 TIE1

SCAMP4 ADAT3 RUFY3 PREPL NEUROG2 CENPT C1orf194

CEACAM21 RNF150 KYNU ACSL1 NECAB2 ZNF687

ABHD12 RANBP9 TTN ABLIM2 NTN3 CGN

ETS2 MTFR2 GPR148 ARSJ CORO1A RRNAD1

TMEM242 TPST1 RSAD2 PCDH10 SLC38A8 DDOST

CCBL1 LINC00208 CEP68 SMAD1 LOC400558 THEMIS2

TFAP2E LINC00092 CAPN10 ARFIP1 PIGQ ZMYM1

LEPREL2 TDRD7 FAM228A TMPRSS11F ZNF843 TAL1

USP7 NUP214 DNAJC27-AS1 DCTD AARS C1orf146

HOXB-AS3

HOXB6 DDX31 GPAT2 LRRC14B LINC00304 TMEM56 TMEM56-RWDD3

HOXB9 CLCN6 LOC100130691

ACOT12

RNU5E-1

RNU5D-1 TUBB3 MIR137HG

LINC00482 ECE1 MFF FAM13B DBNDD1 NTNG1

ARHGAP25 FAF1 ARID5A DOCK2 NOXO1 PEAR1

SLA2 PRPF38A ANO7 LOC340073 ZNF689 NR1I3

MIR3687 HS2ST1 PREB PCDHB18 FA2H CD247

LCNL1 VCAM1 LOC728537 KCTD16 ZG16B LINC00862

PSD TOP1P1 GPR155 PLEKHG4B CPNE2 SPATA17

C10orf95 KLHL20 TRAK1 ZDHHC11 DECR2 CCSAP

PAH RC3H1 EIF4G1 MARVELD2 MEFV EDARADD

SYNM IL2RA ITGB5 CPEB4 ESRP2 GPR89A

TTC23 DRGX AHSG CLTB SLC38A8 PRDX3

APOL4 M1 TMEM44 TSPAN17 C16orf95 SLC39A12

LOC285501 JMJD1C-AS1 JMJD1C HDAC11 SLC6A7 DNASE1L2 C10orf128

AGO4 PPIF MYRIP GRM6 ZSCAN10 SRGN

PTGER3 OPN4 MIR548H2

C1QTNF3-

AMACR

C1QTNF3 RBFOX1 LINC00840

LDHA CNNM1 ATP11B FABP6 NDE1 GPR26

PLBD1 SEC31B STIM2 AACSP1 PAPD5 ZNF438

KLK5 PDCD11 AFF1 DNAH5 C16orf70 ALOX5

CLASP2 PAK1 FGFRL1 CMYA5 ZCCHC14 C10orf54 CDH23

SNX25 SDHD UNC5C PCDHA12 RHBDL1 CYP2C19

MYOM3 MSANTD2 GAB1 GABRB2 SLC7A6 C10orf107

FAM71A GLB1L3 LOC402160 TMEM232 CLCN7 MMP21

RASSF4 TEAD4 MIR4798 PCDHA6 ABAT HABP2

PPP6R3 POU6F1 RBPJ PCDHA11 ZC3H7A SLC25A16

C14orf64 XRCC6BP1 ANKRD50 CDX1 ITFG1 PHKB ACSL5

YPEL3 FRS2 KLF3 FAM193B TOX3 DYDC2 DYDC1

C2orf71 ALDH2 HS3ST1 WDR41 SF3B3 SLK

L3MBTL2 SBNO1 FRAS1 CMYA5 USP10 LOC100188947

N4BP2 RXFP2 DUSP1 MCTP1 FAM92B HHEX

RPL19P12 SLITRK5 SH3TC2 SLCO6A1 SSTR5 SLC18A2

KIAA1522 PSMA3 PRR7-AS1 CSF1R SSTR5 SSTR5-AS1 KAT6B

TMEM53 GOLGA8B NREP C5orf64 IFT140 PTEN

FKBP4 CDAN1 PRR7 FAM151B NAGPA-AS1 EXOSC1

SCAND2P PYGO1 GHR GRM6 SCNN1B ZNF503-AS1

MPHOSPH6 ANP32A EIF4EBP3 PIK3R1 CHP2 LZTS2

PNLDC1 KIAA1024 SIMC1 POU4F3 ZFHX3 TMEM72 TMEM72-AS1

LHX6 ZFAND6 CNOT6 CDX1 CTU2 TMEM26

UBE2D1 HAPLN3 EXOC3 GFPT2 ZNF276 TTC18 DNAJC9-AS1

DLG5 UNC45A ZNF608 MIR143HG KLHDC4 RBP3

GLB1L3 SMG1P1 PHF15 PCDHGA2 AFG3L1P ZNF518A

CAMTA2 GSG1L DPYSL3 CD74 THRA RRP12

SLC39A3 ZNF629 LMAN2 ATG12 LINC00511 FLJ46300

MXD4 FBXW10 ST8SIA4 GLRA1 ELAC2 AKR1E2

RELL1 AKAP10 KIAA0825

BASP1

LOC285696 WNT9B ANK3

LGSN PTPN2 PCDHGA12 PAIP2 MIR635 TMEM180

MIR548T CNTNAP2 ROCK1 SFXN1 PCDHGA11 ANKFY1 NRP1

CYB561D1 DAPK3 TBC1D22B SYNPO PIRT C10orf53

PSD ZNF333 CCND3 SOX30 NLE1 MAT1A

SLC2A13 ANKRD27 CLDN20 ITGA1 PSMD12 ITGB1

SSH1 CEACAM5 GSTA5 ARL15 SCARF1 CCDC147

ELMO3 IRGC DST OCLN GRIN2C ACY3

LGALS9 DKFZp434J0226 HIST1H2BD FEM1C C17orf99 RHOG

PIGS ROCK2 ALDH8A1 MARCH3 RAC3 MS4A15

TMEM98 LOC442028 PI16 RAPGEF6 FOXK2 FOSL1

RSAD1 ICA1L PTCHD4 PCDHAC1 ZBTB4 TTC17

TMEM235 CD28 NOX3 PCDHAC2 G6PC3 MRGPRF

CHST9 EPHA4 FAM184A SLC36A2 09-sep DNAJB13

KCNG2 VPS16 TNFRSF21 RAI14 FLOT2 WNT11

PARD6G DDRGK1 CNKSR3 MIER3 LASP1 CCDC88B

TAF1B APMAP QKI MRPS27 ARHGAP27 JRKL-AS1

TMEM189

TMEM189-

UBE2V1 BCAS1 PDAP1 FAM169A

MARCH10

MIR548W TMEM80

MX2 GART JHDM1D

RNU5E-1

LOC100131067 RNU5D-1 KSR1 DDX6

CBX6 GUSBP11 KCP ATG10 ANKRD13B TSPAN4

RANGAP1 SREBF2 SMARCD3 CCNH TEX2 FXYD2 FXYD6-FXYD2

PARVG KLHL18 ANLN STARD4-AS1 ADORA2B HYOU1

CCDC13-AS1

CCDC13 POC1A CDK6 PCDHA9 FAM83G AMPD3

FAM198A CADM2 ZCWPW1 PDLIM4 TMEM11 TBX10

LOC157273 FAM194A MIR4648 SOWAHA ELP5 BARX2

NPDC1 KPNA4 GATS PCDHGA7 MIR1180 LRRC10B MIR4488

CPSF3L ATP13A5 WBSCR22 CDX1 ZNF207 WDR74

VPS37B TRMT44 MIR4648 LTC4S

MIR338 MIR657

MIR3065 SYT12

NFATC4 PHOX2B NAMPT GMDS FAM83G INSC

YBX2 GUCY1A3 SMO TJAP1 MAPK7 B9D1 FLJ42102

ZNF701 NIPBL UBE2H ELOVL2 KCNJ18 TPBGL

NCOA1 VDAC1 FAM185A ZNF318 VEZF1 POU2AF1

SOD1 CDKL3 LRRC61 LRRC1 RPL38 ATHL1

ADORA2A-AS1 KLHL3 RAC1 HIST1H3A LOC100506388 KLC2

VIPR1 BPHL

ZFAT-AS1

ZFAT SLC26A8 MINK1 GRM5

NPR3 TMEM170B SBSPON GUCA1B RNF135 SCUBE2

CA9 HIST1H2AG GPAA1 PNPLA1 LRRC37B SOX6

MELK TTBK1 PNOC LOC100507194 CYB561 SLC1A2

MATN1 ATG5 LZTS1 PTCRA USP6 SLC15A3 ADARB2-AS1

ADARB2 PEX7 DEPTOR MLIP

MIR4520A

MIR4520B FNBP4

CCNY SF3B5 CRH SMIM13 GPS2 ST5

LOC440311 EPM2A PYCRL METTL24 MPDU1 SPI1

RNFT1 OPRM1 LYNX1 WISP3 B9D1 LGALS12

C19orf55 MAP3K4 CDCA2 KIAA0319 SMTNL2 GPR137

TFIP11 FAM120B PTK2 TULP1 SLC16A13 SLC29A2

SEC62

HOXA10-HOXA9

HOXA10 S1PR3 MIR4462 SHISA6 THY1

DOCK5 PINX1 APTX CCR6 KCNJ12 LOC283194

TP73-AS1 DPYSL2 01-dec RRP36 MPO ROBO4

PRELP NCOA2 CIZ1 MYLIP ACE PCF11

DCHS1 LY6K SOHLH1 PRPH2 FAM104A TSG101

MICALCL KIAA1432 KIAA1984 GNMT DUS1L LRRN4CL

CD63 LOC100133920 PHYHD1 PPP2R5D RAB40B P2RY2

HIGD2B BBS4 INVS TPRN ZBTB2

PLSCR3

C17orf61-PLSCR3 CRTAM

09-sep C9orf84 TJP2 DUSP22 STAT5A RRAS2

TAF4B SH2D3C POMT1 TFEB LOC284080 C11orf86

CLIP3 DDI2 NOXA1 COL9A1 CD79B DRD2

GSK3A WDTC1 ECHS1 SERPINB6 LOC100507410 FLI1

CCDC93 PDE4DIP CASC2 HIST1H3H GRAPL FAR1

C2orf27A LCE3D SUFU DAAM2 CACNB1 SPI1

LOC151174 LY9 SKIDA1 ME1 LOC100130581 PLA2G16

LINC00029 POGK PFKP KIAA1244 TOM1L1 METTL7A

MIR4761 IL19 LINC00202-1 KCNK5 C17orf82 MYL6B

MST1R RBM34 FAS STX11 LOC100130370 PLEKHG6

CPA1

ST8SIA6

ST8SIA6-AS1 SUFU DDO ALOX12 ATF1

AGPAT6 PNPLA2 C10orf71 UHRF1BP1 ASGR2 FLJ12825 IQSEC3

LOC574538 NAP1L4 BNIP3 TSPYL4 MFSD6L TBC1D30

LECT1 ZNF408 ACBD5 ADGB DRG2 LRRK2

PRSS27 ZFP91-CNTF ZFP91 TMEM72 VOPP1 ALDH3A2 RHOF

ZG16B CCDC86 EXPH5 ACTL6B HSPB9 TMEM52B

SP6 XRRA1 MIR130A POP7 BZRAP1 SELPLG

HOXB-AS3 SLCO1B1 NLRX1 WDR86 SOX15 TRPV4

MC2R KRT72 TPCN2 HOXA3 RASL10B ASIC1

MCEE POLR3B C11orf70 MIOS SLC4A1 BCAT1

CLCN3 GJB6 KDELC2 GUSB PPM1D COL2A1

CPA5 SOX1 CD81 ZP3 TBX4 COPZ1

CLCN4 GAS6 MOB2 CTSD NUB1 USP36 MARS

UTP11L UPF3A NADSYN1 ZP3 ULK2 FZD10

CSRP1 CBLN3 PPP2R1B FASTK UNC119 FMNL3

AP3M1 ZFYVE1 C1QTNF4 HOXA5 LHX1 SOCS2

ADAMTS8 SNORD116-8 LOC100133315 WBSCR22 LOC146880 GIT2

NTF3 KLHL25 SLC22A18AS TECPR1 ST6GALNAC1 GCN1L1

LOC642846 FES EHBP1L1 ZNF394 C17orf70 TENC1

TRIM9 CD300A TMPRSS4-AS1 LOC100130705 NARF BEST3

CDK10 OVOL3 IFITM3 ABCF2 C17orf66 HMGA2

FSCN2 PLEKHA4 MRPL23-AS1 LOC100288524 NBR2 CCDC42B

C19orf24 NLRC4 SYT9 FZD9 CDC27 LMO3

ANKRD62P1-PARP4P3 EPC2 MIR5692A1 IQUB CDK5RAP3 AEBP2

LOC401052 XRCC5 DCDC1 NUPR1L ITGA3 SMARCC2

NQO2 CRYBA2 ST3GAL4 CLDN3 CA10 FOXN4

COX19 WRB LTBP3 NSUN5P1 HEXDC CABP1

NOM1 KREMEN1 KCNJ5 LRWD1 DHRS7B CPNE8

PSCA TST DYNC2H1 DOCK4 LOC440461 KIF21A

SLC25A25 FBLN2 HMBS TPK1 SHISA6 FAM222A-AS1

SLC27A3 LRRFIP2 GYLTL1B ABCB8 MEIS3P1 PTPN6

CHAT C3orf67 CST6 NCAPG2 HAUS1 FAM222A

STAB2 LINC00636 MCAM PSMG3 C18orf25 ABCC9

MRPS31 OSBPL11 LRP4 EPHB4 GNAL DDX11

KBTBD13 C3orf22 UBE2L6 UFSP1 TGIF1 FGD4

GAA CHST2 EML3 ATG9B SMCHD1 ACVRL1

MYOM1 LRRIQ4 B3GNT1 NPC1L1 IMPACT KRT85

GALR1 CCDC50 LSP1 CUL1 ZNF521 TCP11L2

DNAJB1 LOC285419 C11orf68 ABP1 L3MBTL4 FAM109A

TNNI3 RBM27 B3GNT6 SKAP2 LDLRAD4 KRT83

DNAH6 DTNBP1 MTCH2 ORAI2 AQP4-AS1 RPL6

SUMO1 SOX4 AHNAK KCNH2 LOXHD1 SNRNP35

SNX21 ARMC12 LTBP3 LOC442497 LDLRAD4 PLEKHA5

KCNJ6 BAG2 BBS1 HOXA4 TCEB3B NAV3

AMIGO3 MDN1 PXMP2 VPS41 MBD2 RILPL2

RASSF1 FRK FAM222A ICA1 PHLPP1 POLR1D

RYBP PHACTR2

FOXM1

RHNO1 DGKB KDSR HMGB1

PPP1R14C SLC25A13 SSPN LEP MC5R PCDH20

DIRAS2 ZKSCAN1

LTBR

SCNN1A ZNF853 KIAA1328 HSPH1

DCST2 LOC100216546 SLC41A2 IL6 MOCOS AKAP11

TMCC2 SLC4A2 SLC16A7 HOXA7 LOC284276 TUBA3C

KCNC1 SMIM19 SMCO2 GBX1 LIPG DLEU2 TRIM13

CAPN1 MTBP KRT72 WIPI2 TCF3 TEX26-AS1 MEDAG

N6AMT2 GLIPR2 NAB2 ADCYAP1R1 LOC644189 LINC00552

CES3 ALDH1B1 GRIP1 AMPH TINCR XPO4

ACOX1 MXRA8 KCNA6 FAM200A KLF16 FLT3

BTBD2

ACOT11

FAM151A LINC00507 CALD1 MAG TSC22D1

PRAM1 NBPF9 STX2 CCM2 IFNL4 MTIF3

MIR641 UAP1 KCNA5 CCDC146 ZNF816-ZNF321P LINC00565

ZFP28 PTPLA IRAK3 PODXL DMKN SMIM2-IT1

CCDC12 LINC00842 HCAR3 ZNF398 RINL B3GALTL

LOC100129550 C10orf2 KCNH3 DPP6 DBP SERTM1

FAM81B KAZALD1 MED21 PHF14 RASIP1 HNRNPA1L2

C8orf31 CASP7 YARS2 HOTAIRM1 SIGLEC7 LINC00457

KIAA1958 DUSP16 DDIT3 NUDCD3 ZNF578 GPR68

GALE H1FNT ACSM4 GTF2I ZNF414 ACIN1

C1orf168 PRKAB1 GGACT CTTNBP2

ZNF559-ZNF177

ZNF559 SERPINA10

USP21 FGF9 C13orf35 AKR1D1 RAB8A METTL3

VSIG2 PCDH8 RAB20 GALNT11 DMWD FLVCR2

RHOV OTX2 C14orf80 ESYT2 MBOAT7 EFCAB11

WDR61 TGFB3 STXBP6 ZNF680 MKNK2 PRIMA1

THAP11 EHD4 EFS C7orf61 TIMM44 MAX

CBX4 NEDD4 PYGL CUX1 SMARCA4 DNAL1

SLC25A10 CRYM-AS1 DEGS2 PNPLA8 DKFZp566F0947 LGMN

GCGR EIF3C WARS BRAT1 RASGRP4 SCARNA13

KHSRP CYLD CPNE6 TFPI2 C2CD4C APOPT1

CECR1 CCL17 TTLL5 PPP1R9A KANK3 SERPINA6

A4GALT WIPF2 AHNAK2

ATP5J2

ATP5J2-PTCD1 ADAMTS10 LINC00226

CHST13 NFATC1 MAPKBP1 MUC17 PRX MYH7

FLJ36777 LPPR3 CT62 FOXP2 CDC42EP5 TMED10

ING2 CHAF1A ODF3L1 MGAM ANKRD24 BTBD7

KDM1B PLEKHG2

C15orf56

PAK6 CLCN1 ZNF700 NUBPL

EEPD1 WASH2P CHP1 SDK1 PGPEP1 CRIP2

LCN8 TUBA3E BMF ANKMY2 LOC148145 GNG2

KTI12

TXNDC12 BMPR2

JMJD7-

PLA2G4B

PLA2G4B SEMA3C CHST8 DHRS7

SLC6A13 EFHD1 LOC283663 PILRB LOC400685 CEBPE

GALNT6 EMILIN3 STRA6 LRCH4 SPHK2 REC8

WASF3 B4GALT5 NR2E3 ACHE IZUMO2 LRRC9

PMFBP1 JAM2 DUOX2 TMEM209 PNMAL2 ZNF219

OTOP2 PITPNB RHOV SLC13A4 RRAS MIR208B

NPAS1 AP1B1 CD276 CDCA7L CELF5 DCAF4

CENPB RBX1 KIFC3 C8orf74 CLPP KIAA0125

SLC12A8 CAMK1 OGG1 TBC1D24 MROH6 RAB11B PPP4R4

PSAPL1 UBE2E1 LOC81691 BMP1 PLD3 ATG2B

PROB1 LAMB2 PLLP SDC2 KCNN4 LINC00617

PCDHB12 TLR9 ATP2C2 PSCA HSPBP1 APBA2

CD109 ZBTB11 PSKH1 PARP10 ZNF132 GOLGA6C

ZNF107 GTPBP8 TPPP3 HSF1 SLC25A23 LINS

WBSCR16 RAB6B KIAA0513 RBPMS C3 VPS18

DOK2 TRIM38 BAIAP3 LOC100506990 PNPLA6 TP53BP1 RNU6-28

FRRS1 GABRR1 PRMT7 INTS9 LRRC8E SQRDL

PBLD SEC63 SYNGR3 RUNX1T1 PRKACA ISLR

MOB2 IFITM10 NUP43 LOC732275 KIAA1456 TDRD12 FAM63B

MYO1H MAD1L1 TMEM204 RHOBTB2 APLP1 VPS13C

HNF1A ADAM22 C16orf11 FAM83A LOC100507433 CHD2

RPUSD1 REPIN1 CENPN MTMR7 PLAUR TM6SF1

TPSG1 MIR153-2 PDK2 TP53INP1 SYCE2 MAN2A2

CHST6 CDH17 ACSF2 GPIHBP1 RPL18A ISL2

EFTUD2 ZNF696 ARMC7 PDLIM2 AP1M2 ISG20

GFAP MPDZ PLEKHM1P LEPROTL1 MIR548O2 NCR1 DENND4A

MFSD11 FAM74A3 NR1D1 LAPTM4B C19orf77 NOX5 MIR548H4

VSTM2B C9orf41 KRT15 EEF1D LINC00665 HERC2P10

BLVRB LOC100128593 WDR81 DLC1 EXOC3L2 TMOD3

LOC728730 PTGDS STAC2 EIF4EBP1 OPA3 PEAK1

ARMC9 MRPL20 MIR4729 ADAM2 SUV420H2 MESDC1

AVP THAP3 JMJD6 LOC100507632 GNA15 AP3B2

KLHDC7B RTCA IGF2BP1 WWP1

CCDC159

TMEM205 CERS3

COL8A1 MIR548G FMO5 EPN3 PLEC TNPO2 PLCB2

LOC100507391 SYT15 TMEM107 BRF2 GADD45GIP1 CHAC1

FAM53A IDE PIP4K2B OSGIN2 SHISA7 GNB5

LOC100133461 LINC00294 AKAP1 KIAA1875 LMNB2 FBXL22

C4orf19 PPP1R32 04-sep HTRA4 C19orf70 ANKDD1A

NUDT1 FTSJ2

HNRNPUL2-

BSCL2 BSCL2 SMARCD2 PENK EPHX3 BLM

FAM133B

FAM133DP RSF1 LRRC45 EIF3H SLC35E1 SNORD115-22

NYAP1 LOC100288346 SNORD124 SLC39A4 MAP1S ACSBG1

LOC729732 LOC100506990 SPIC BTBD17 PDLIM2 TMEM190 GABRA5

TP73-AS1 SPERT MXRA7 DPYS ZIK1 ADAM10

LOC283299

MIR548AN

UBAC2 ATAD5 OXR1 SCAMP4 SNORD115

HYLS1 BMP4 FBF1 PLEC BST2 ACAN

ADIPOR2 C14orf2

FAM211A

C17orf76-AS1 C8orf42 FFAR1 PRSS30P

C12orf23 DISP2 KRT18P55 LPL MYPOP CENPN CMC2

GALK2 BNIP2 KAT2A CHRNA2 KLK12 LITAF

TPM1 SNAPC5 MAP3K14 SFRP1 ZNF331 DCUN1D3

MEF2A CRTC3 SYNRG ESRP1 CACNG6 FOXF1

HBQ1 ERCC4 TBX21 ZFAT ELANE HAGHL

SLFN12L CCDC135 CHAD SOX17 UBXN6 QPRT

EFCAB13 TMC6 SUMO2 ATAD2 ATG4D SYT17

ZNF575 FLJ22184 SLC52A1 OPLAH LPPR2 ATP2A1

TRIM28 ZNF490 MFAP4 UCK1 PRKD2 SRL

PLCL2 PSG11 MIR4726 PBX3 SULT2B1 CETP

MIR128-2 RELB FMNL1 ATP8B5P

ZNF816-ZNF321P

ZNF816 RRN3P2

HEMK1 C3orf18 ADCY3 SGSH MAMDC2 ONECUT3 HSF4

SHOX2 DCTN1 ALOX12 LCNL1 KIAA0355 VWA3A

SLC7A14 NEB PTRF NSMF MLL4 LOC595101

TTBK1 FZD7 ENTHD2 NIPSNAP3B CD79A BANP

PCOLCE GPR55 SERPINB2 ZCCHC7 TMEM145 LOC100287036 ANKRD11

WDR38 TM9SF4 NAPA-AS1 NAPA COL15A1 GIPR SNORA64 SNORA10

LCN9 CNBD2 NUMBL ZNF462 MIR548Q AP2S1 PRSS41

FGFR2 PIWIL3 MYBPC2 PPP6C PRPF31 ZNF19

SMAGP APOBEC3C SEC1P UAP1L1 PCSK4 SLC6A2

MIR5692B FEZF2 CEBPA-AS1 GPR107 MBD3 CDH16

CHRNB4 UBA3 ADCK4 AMBP GNA15 RHOT2

RGS11 ACPL2 PRG1 TSC1 PLIN5 ACSM5

HS3ST6 LRCH3 KCTD15 DMRT1 ANGPTL4 SCNN1G

FAM211A DCK LOC400685 DNAJB5 BEST2 DOC2A INO80E

DHRS13 WWC2-AS2 ZNF57 CCDC180 NFIX MT1DP

ETV4 DNAH5 TRPM4 FAM129B ZNF728 ATP6V0D1

KCNH6 DAB2 RPS19 FNBP1 PPP1R13L SPG7

CCDC68 DDX46 NLRP2 C9orf169 FAM83E PRDM7

FBXO17 SLC35A4 BSG TUSC1 PTOV1 FAM86A

RPS5

HIST1H2AM

HIST1H2BO RNF126 NPDC1 NLRP12 C16orf96

DOCK10 MAN1A1 TJP3 CORO2A TICAM1 KIAA0430

MX1 CHST12 APOC1 UGCG

LOC100996307

LIPE NDUFAB1

MCAT SUN3 DHDH ORM2 CCDC8 CYBA

LOC100133461 ANKIB1 RASGRP4 UBAP1 SAE1 BEAN1

CXCL1 ACN9 NLRP7 MIR3134 KCNA7 LOC100130894 VAC14

PCDHA4 PLOD3 PRTN3 RABEPK RCN3 C16orf90

IMPDH1 NKX3-1 C19orf77 GAPVD1 FPR3 RANBP10

LOC407835 NEFM CDC25B LHX3 GPX4 CFDP1

CDK20 LOC642236 CSRP2BP FAM219A ARHGAP33 MBTPS1

BICD1 SURF1 BCL2L1 TRPM3 FKRP MLST8

NAP1L1 LIN28A ZGPAT HABP4 SEC1P NTN5 USP31

PRTG MTF1 WFDC5 RAPGEF1 FCGRT ZNF785

GNG13 CNIH4

RTEL1-TNFRSF6B

RTEL1 MAMDC4 NAPSA COX6A2

OSGIN1 AKR1C2 JPH2 SLC28A3 PRKCG TPSG1

SNHG16 ARHGAP21 SS18L1 RGS3 EPS8L1 AMFR

C19orf45 SPOCK2 UCKL1 GOLGA1 CDC34 DYNC1LI2

WFDC2 SCYL1 PKIG SH2D3C ACSBG2 CIRH1A

PRODH BSX RSPO4 CRAT GPI FOXC2

MYL3 FEZ1 GNAS SURF1 SURF2 ZFP36 ABHD15

LOC100302640 LPCAT3 FERMT1 ADAMTS13 CYP2A6 RAP1GAP2

LOC100129931 NUAK1 EPB41L1 GALNT12 TTYH1 ALDH3A1

DPPA5 PUS1 EEF1A2 KLF4 LILRA1 PDE6G

KIF25 MTUS2-AS1 MTUS2 NKX2-2 SVEP1 DNAAF3 ATP6V0A1

BBS9 CLDN10 CCM2L C9orf106 ZSCAN18 FAM171A2

CPNE3 CLDN10 RALY RNF208 HAUS8 BZRAP1-AS1 BZRAP1

DCAF13 AVEN PPP1R16B DOCK8 FBXO17 SMG6

TMEM54 TRADD ZNF831

CCDC180

LOC100499484-C9ORF174 UBE2M GPR179

TMEM48 CNTNAP4 SSTR4 C9orf62 C20orf96 FZD2

LOC100527964

LHX4 IRF8 CYP24A1 FOXB2 BPIFA4P UNC13D

TSPAN15 SNAI3-AS1 COL18A1-AS1 TMOD1 UQCC ARRB2

WEE1 TNFRSF13B BACE2 LINC00094 GPCPD1 TBX4

C11orf58 LOC100653515 CSTB SLC35D2 RBL1 SLC9A3R1

LOC100499227 KCTD1 MAPK1 PTGES2 PMEPA1 TMEM235

CPM SAMD1 TEF SIT1 MYLK2 VMO1

PKM DRC1 PISD GNA14 MIR499A MIR499B CACNA1G-AS1

AGPHD1 FSHR CYB5R3 KIAA0368 LOC100505783 SLC16A3

ZNF555 LBX2 NF2 TPRN SLC13A3 PYY NAGS

ZNF283 AOX2P

CECR5-AS1

CECR5 PCGF5 PDRG1 HLF

HIF3A MARCH4 RFPL2 KIAA1217 WFDC3 SREBF1

ZSCAN18 PRSS56 CHADL LOC100130539

LOC100130264

SLC24A3 LINC00469

LOC100131691 MZF1 CPXM1 PARVB KCNIP2 BPIFA3 CCDC42

PKP4 GGT7 SUN2 AGAP11 MMP24 MGAT5B

MIR3648

MIR3687 HIC2 USP18 C10orf90 LZTS3 PHF12

C21orf59 GGT5 DGCR6 EBLN1 SLC9A8 LEPREL4 FKBP10

C21orf2 DNAH12 NOL12 PDCD11 TCEA2 MPP3

KRTAP10-2 SYNPR

PRR5-

ARHGAP8 PRR26 COL20A1 CD300LG

RNF212 SMIM20 TMEM255A PNLIPRP2 PRPF6 COIL

KIT SULT1B1 BCAP31 ZNF365 RBPJL SLC2A4

AGXT2L1 FIG4 KAL1 PPAPDC1A MAPRE1 NFE2L1

CETN3 NUP205 FGD1 DOCK1 NNAT TEX14

CCNJL SHC3 WWC3 DUSP13 NNAT MYO15B

HOXA10 ST6GALNAC6 ITIH6 METTL10 CASS4 CANT1

DNLZ KIF17 AK4 GPR158-AS1 GPR158 CEP250 KRTAP2-1

GPM6B ECE1 CNTN2 KIAA1462 NKAIN4 UNK

FBXO44 HCRTR1 PLA2G2C FAM13C VSTM2L C17orf104

RNF186 TNFAIP8L2 FCN3 MMRN2 SPATA2 LOC440461

TMEM56-

RWDD3 NVL PPT1 FOXI2 COL9A3 SRP68

SLC22A15 TTC40 ARPC5 PRKCQ BPIFB2 SENP3-EIF4A1 SENP3

CR1L DTX4 ALPL CCDC3 C20orf166-AS1 FAM20A PRKAR1A

DNHD1 SPSB2 SPATA6 C10orf76 FAM110A PITPNA

CADM1 ARHGEF25 FCRL6 PITX3 TGM3 WFIKKN2

CHD4 SLC5A8 TAS1R1 NOL9 PROSER2 C20orf196 LINC00469 LOC400620

SPESP1 ASCL4 CAPN2 NSUN6 SNAP25 HN1

TEKT5 FICD USP48 KIAA1598 PLK1S1 CCDC144A

NLGN2 ZMYM2 GUCA2A FAM178A CBFA2T2 PIPOX

LRRC3C SYNDIG1L FAM69A LDB1

STX16 STX16-

NPEPL1 TBC1D3P1-DHX40P1

HKR1 ZDHHC22 PDIA3P FRMPD2 NELFCD AANAT

SIGLEC14 LOC283683 ZBTB7B BTRC LOC149950 EIF4A3

ZNF331 WFIKKN1 ADAM15 VENTX DLGAP4 BAIAP2 BAIAP2-AS1

KIDINS220 CHTF8 PIGR PIP4K2A SOGA1 SNORD42B

MRPL33 EFCAB5 SLC2A5 NODAL DZANK1 NUFIP2

CNTNAP5 C1QTNF1 C1orf127 TDRD1 PROCR DBF4B

FAM83D URI1 ZMYM4 USP6NL ZFP64 MIR4316

LOC388813 C2orf53 CYP4B1 MKX DOK5 MIR3186

DGCR8 EHD3 AKNAD1 CDHR1 GATA5 ZNF232

COPS4 VPS54 SEMA6C ACTA2 C20orf26 RPL29P2

MRPS27 PTCD2 PPP3R1 LEFTY2 PRLHR

PLAGL2 POFUT1 NT5M

RRAGD RBM38 GPR137B

FAM24B-

CUZD1 LOC399815

FAM24B SLC32A1 RPL27

IL7 C2CD2 UBAP2L PDE6C TNNC2 MAP3K14

CCDC166 BCL2L13 IGSF9 BTBD16 TCFL5 ZNF236

C9orf129 TGM4 TRIM58 UTF1 BHLHE23 RNF165

WIF1 GPR27 SCNN1D HNRNPF IFT52 CDH7

NALCN SENP5 FAM213B MMEL1 FBXL15

RBM38 MIR5095 ABHD3

ASPG FGA TNFRSF25 RBM20 GATA5 CLUL1

NIPA2 SRD5A1 SLC25A34 CSTF2T TPD52L2 CCDC102B

LINC00593 LOC642366 PHC2 HERC4 SMOX SNRPD1

C15orf59 FLJ46906 LDLRAD1 C10orf105 E2F1 CDH2

LYSMD4 LOC100132352 ACOT7 XPNPEP1 MATN4 COLEC12

PGP TUBBP5 FMO5 SPOCK2 TFF1 TMEM241

PRSS36 NKAIN1 ADIPOR1 KCNMA1 TMEM50B RBBP8

KXD1 SPOCD1 FLAD1 MMS19 RRP1B HSF2BP DSC3

RNF149 MTMR9LP LOC100131234 C10orf95 PCP4 NETO1

ARPP21 CELSR2 MFSD4 SORCS3 LOC100133286 SALL3

ENTPD3 OLFML3 PUSL1 SORCS1 KCNE1 EIF3G

GPR62 GON4L C1orf86 EIF3A

LRRC3-AS1

LRRC3 F2RL3

DPPA2 KDM5B MUL1 PTF1A CHODL TFPT PRPF31

HDAC3

OBSCN

C1orf145 PODN CTBP2 USP25 P2RY11

MAT2B DUSP5P1 RHOU BCL9 MUC5B CLIC6 EVI5L

LINC00473 ANAPC16 CREB3L4 DKK3 GRIK1 TNNT1

T FAM35A LAMC2 CABP2 LOC339622 RPS15

NAPEPLD ARCN1 LAD1 RAB30 OLIG2 ISYNA1

SVEP1 ADAMTS20 TAS1R3 MOB2 DUSP8 SLC5A3 STRN4

CCDC30 SLC24A6 ICMT TH KCNJ15 PRSS57

TFB2M GPC5 RCC2 MRGPRG-AS1 ABCC13 MIR4745

NKX6-2 FGF14 CELA3A MRGPRE CARD10 ZNF781

LOC100128239 PPP1R14D WASF2 CHRM1 CYB5R3 CLEC11A

CCND2 GABPB1 FOXJ3 CABP2 RNF185 SIGLEC17P

ORAI1 RAB11A EPHX4 UNC93B1 RIBC2 SULT2B1

LOC100128770 MT1DP COL11A1 ST5 SGSM3 FXYD5

ZFP1 CCDC47 MROH9 SCGB1A1 ASCC2 MVB12A

SCN4A HID1 C1orf233 C11orf30 TXN2 SNORD32A

MRPL35 MEIS1-AS3 KAZN PIWIL4 UBE2L3 KLK6

SCN2A INHBB C1orf94 RIN1 CABP7 RETN

OGG1 NABP1 SF3A3 DDB1 SSTR3 RSPH6A

AGPAT9 SP140 RHBDL2 ARAP1

MIR4763

MIRLET7B FBXW9

SLC1A3 GGTLC1 HPCAL4 CYP2R1 KLHL22 SLC1A5

PCDHA4 MROH8 LINC00466 MIR1237 LRP5L CD320

HIST1H2AL KCNS1 CACNA1S CHKA PVALB KANK3

SMC5 MORC3 MIA3 FAT3 IL17REL HAPLN4

CNIH3 ZNF74 UBE2J2 SNX19 MCM5 FUT6

ABCC8 FBXW4P1 MMP23B OPCML APOBEC3H RTBDN

OVOL1 SEC14L3 ARHGEF19 PTPMT1 KBTBD4 MAPK11 GCDH

PHOX2A PKDREJ TMEM54 TAF6L ST13 CLEC17A

NBEA

MIR548F5 DNASE1L3 B4GALT2 RAB1B CECR1 FOSB

DLEU7 SDHA ACOT11 PKP3 LOC100128531 KLK10

CHEK2P2 TRIP13 MRPL20 FAM168A SLC35E4 LAIR2

LOC283692 CCNI2 RFWD2 ENDOD1 ZC3H7B PLIN3

PARN PCDHB16 ADCK3

CTNND1

TMX2-

CTNND1 BID RAB3D

FOXL1 PCDHGA9 ARF1 AAMDC ZNF70 ZNF442

ADCYAP1 ARSI TP73 RNU6-83 LOC150381 USHBP1

LOC284260 DUSP22 SERINC2 TP53AIP1 AIFM3 LRP3

ST8SIA3 RPL10A PVRL4 DRD4 ZBED4 S1PR2

MBOAT7 GUCA1A NEK7 RAB6A APOL5 CEACAM3 ZNF606

LOC100128398 LOC100287632 ZNF672 QSER1 SLC25A17 LOC100505622

LOC440900 LOC100289495 PARK7 PSMC3 XPNPEP3 IL4I1 NUP62

PECR CCDC129 UBR4 NDUFS8 DEPDC5 ZNF444

PABPC1L CDKN2A CDKN2B-AS1 OPRD1 KCNJ1 TPTEP1 EPOR

MAATS1 TGFBR1 LRRC8D B3GAT1 IGLL1 AKAP8L

ZNF141 SUSD1 AMPD2 ATHL1 SLC2A11 LSM14A

SMPDL3A TTC16 AIM2 ART5

UPB1

ADORA2A-AS1 FAM83E

POM121 GSTM3 RGL1 ARNTL RASL10A TULP2

C9orf170 LOC440600 CNST PTPN5 PICK1 ZIM2 PEG3

HIST2H2BA CCDC172 PLEKHN1 CEND1 LOC730668 DIRAS1

WDR64 RFX4 NPPB

TOLLIP

LOC255512 GP1BB DOHH

SLC18A3 TM9SF2 FLJ37453 MRGPRE RAB36 ZFP14

FGF4 TTC9 CNR2 ALDH3B1 HPS4 ZNF665

STUB1 ZSCAN10 NKAIN1 RELT GTPBP1 SLC25A23

CNTROB VMAC GNG12 EED CBX7 ANGPTL6

HOXB4 ISYNA1 KCNA3 CBL CHKB-CPT1B CPT1B TRMT1

MOCOS ARMC6 RCSD1 PAMR1 PNPLA5 CC2D1A

MPND RINL RASAL2 MTA2 PDZD4 ZNF829

CYP20A1 TTC7A KLHDC8A P2RY6 LOC100873065 PEX11G

NCOA5

MIR663B

ANKRD30BL VWA1 AP2A2 KIF4A DKFZp566F0947 MIR3648

MIR3687 LYPD6 HPDL MPPED2 CTPS2 HAS1

RNF123 STAT1 NSUN4 PRR5L LOC92249 RAX2

PCYT1A PLEKHM3 C1orf105 SLC22A11 HAUS7 PRAM1

GALNTL6 CYP27A1 SHCBP1L RBM4 PCDH19 C19orf66

MRPL36 NDUFS6 TFF2 C1orf106 AMOTL1 LOC286467 ZNF563

FHL5 IL17RA RBP7 SLC22A12 BCYRN1 ZNF709

REPS1 TTC28-AS1 FBXO2 LRFN4 PLXNB3 HSH2D

PDE4DIP CCDC13 EMC1 PC IL1RAPL1 FKBP8

FAM204A C4orf22 SESN2 DIXDC1 PCDH11X GRAMD1A

NDRG2 TBC1D9 ZNF684 NUP98 PPP1R3F SPRED3

PGPEP1L ANKDD1B ERMAP NLRP10 PNMA3 CPT1C

GAS8 FBLL1 SYT6 LTBP3 IRS4 SBNO2

MYO1C DUSP22 IGSF3 NPAS4 PPAP2B PTPRS

ANKRD30B GPR146 ADAMTSL4 PGR LOC101054525 LPAR3 STXBP2

GIPC3 TSPAN33 PKLR IRF7 RGS16 ZNF559-ZNF177 ZNF177

ZNF726 FNTA CCDC19 BDNF ATP1B1 MRPL4

ZNF30 FLJ46284 RYR2 SLC39A13 LAPTM5 SPC24

ELMOD3 FAM102A PIK3CD VPS51 PSMA5 ZNF526

ERCC3 COPB1 EXOSC10 CCDC83 LOC148709 HIF3A

CCDC140

PAX3 CTSF NUDC DDX6 TNFRSF25 UQCR11

SPHKAP SERPINH1 POU3F1 BDNF LUZP1 C2orf40

PKNOX1 CSRP2 LEPRE1 DCDC5 NUAK2 ANKRD39

CECR7 NTN4 TTC22 FCHSD2 ENO1 HOXD4 MIR10B

SCARF2 FZD10 NBPF7 NPAT ZBTB37 PRORSD1P

IRX2 ANHX LMX1A NTM C1orf200 TSN

SNX18 KL MPZL1 KDM5A BEND7 DARS

PCDHB1 ARHGAP28 LMOD1 PPFIBP1 LRRC20 WIPF1

EEPD1 MIR4748 SRGAP2 FBXW8 LOC100130992 SGPP2

SLC26A5 CHERP PARP1 PRIM1 TACC2 UGT1A

KCNT1 MATN3 TNFRSF4 LIMA1 VAX1 C2orf78

TRNAU1AP ZAP70 PER3 POLE NUDT5 MEMO1

KCNK1 ZNF343 MAD2L2 CDK17 TMEM135 PROKR1

FFAR4

SYS1 SYS1-

DBNDD2 VWA5B1 RPH3A TBC1D10C CYBRD1

UTF1 CECR3 MPL ANKRD13A CTSC GALM

LOC283692 CPEB1 ALG12 PTCH2 ANHX ADRBK1 RNASEH1

ONECUT2 LOC440970 ALX3 WNT5B KCNJ11 WDR54

NTSR2 GHSR RNF115 FOXN4 IL10RA BUB1

EN1 ARHGAP24 PKP1 SCAF11 LOC100240735 STK39

MAP3K19 ZNF827 DISP1 RNFT2 TBX3 HSPE1-MOB4 MOB4

SLCO6A1 IPO11 C1orf35 KRT81 PCBP2 TXNDC9

KLC4 DOK3 NOL9 LOC643770 OAS1 WIPF1

FAM135A

MESTIT1

MEST LOC388692 MTERFD3 HOTAIR MSH2

MUC12 PALM2-AKAP2 VPS45 TRAFD1 HOXC5 HOXC4 FLJ30838

CCDC136 PPP1R26 RHBG

CACNA1C

CACNA1C-AS1 ARL6IP4 LINC00152

ZNF398 FBXW5 C8G DCAF8 TMEM19 SCNN1A PAX8

PAEP PAK3 HSPA7 PHB2 LINC00460 RALB

C9orf169 NBPF10 ABCB10 EMP1 SACS VWC2L-IT1 VWC2L

WLS GNG12-AS1 SH2D2A KRTCAP3 MYF6 ITM2B LOC100506474

ARL3 SFXN2 LINC00856 UXS1 LMBR1L LINC00558 LRPPRC

CTSD ARL3 MIR26B NCKAP5L TNFAIP2 TISP43 LOC646743

TMEM233 HIPK3 HDLBP CD63 LRRC16B WDSUB1

GSX1 SLC35E3 KANSL3 CCDC63 SLC7A8 TANK

CCNK B3GNT4 NR4A2 MPHOSPH9 NFATC4 CFLAR CFLAR-AS1

TRAF4 SLC38A6

MIR149

PP14571 CD163L1 TBPL2 ATG9A

PDE4A AEN WDR33 DDX23 TBPL2 GLI2

QTRT1 FURIN FAM126B AQP2 TMEM229B CCDC74B-AS1

FFAR2 ZNF597 NAA60 BOK-AS1 LHX5 C15orf62 CREB1

RTN4 LOC728392 GLB1L HSPB8 GANC AMMECR1L

MLPH TMEM88 ECEL1P2 LPAR5 C15orf53 COBLL1

POU4F2 FKBP10 USP39 C2orf68 EMP1 SIN3A MIR2467

KRBA1 NPEPL1 STX16-NPEPL1 CXCR2 EIF4B SNORD115-13 PPP1R7

RPS4Y1 KRTAP10-6 RNF144A CTDSP2 RMDN3 C2orf50 FLJ33534

MIR3675

LOC100128531

KIAA1671 SNX17 CLEC9A SLX4 DGUOK

KIF17 EMID1 ECEL1P2 BCAT1 C16orf45 CAB39

FOXE3 SCN10A HPCAL1 LOC100335030 MPV17L NEU4

TAGLN2 ZXDC CERKL CKAP4 SSTR5 FNDC4

RCOR3 FAM153A DHX57 WSCD2 PRMT7 TRMT61B

RNU5F-1 FLJ41649 NEURL3 A2ML1 SCNN1B PCYOX1

PLD5 GPR111 LOC375295 KRT8 RNF157-AS1 ALMS1

SLC18A3 POU3F2 UCN SP1 TRPV1 RGPD1

PAX6 ABCA13 FBXO41 CDK2 PMEL PLCD3 IL1R2

LHX5 TRIM24 ZEB2 BEST3 GP1BA GPR1

LECT1 C1orf172 TBR1 SDS DLX4 TAF1B

FOXG1 MRPL37 CUL3 TRIAP1 GATC LOC284009 PPP1R21

ARNT2 TDRD5 C2orf54 CLIP1 B4GALNT2 AFF3 NR2F2

MIR1469 MICU1 ITGB1BP1 PRMT8 RAP1GAP2 STAT4

CLDN9 SLC22A18 CRIM1 NFE2 C18orf56 HSPE1-MOB4

ATXN2L TMEM179B RAB1A C12orf56 PSMA8 SNRNP200

PARD6A ACD DBX2 MAL DYRK2 ADNP2 RGPD3

SERPINF1 CCDC92 STARD7 TBC1D15 PRSS57 THSD7B

HOXB6 ISM2 HIBCH ERC1 TMEM190 LINC00471

WIPI1 SPATA2L DNAJB2 LRTM2 ZFR2 FMNL2

NR2F6 DHRS11 SOS1 LOC101055625 S1PR5 KCNH7

IGLON5 HOXB2 HOXB-AS1 AAK1 PRPH KLK6 PTPRN

EPN1 NXPH3 SMPD4 TFCP2 FUT6 CAMKMT

KLF11 NFATC1 PRKAG3 SLC4A8 ZSCAN5B MRPS5

SPDYA MIR1227

ASB3 GPR75-

ASB3 PHLDA1 WDR88 CCDC108

CNRIP1 LYL1 CXXC11 FAM222A-AS1 LOC100505495 ZBP1

MIR3196 CCDC97 GPR113 C12orf4 ZNF812 RBPJL

SHISA8 TGFBRAP1

STON1-

GTF2A1L

STON1 METTL20 OTX1 DBNDD2

BIK PLEKHA3 CCDC85A C12orf29 EPCAM PHACTR3

TAGLN3 TFPI RTKN TBX5 ABCB11 TLDC2

ABCC5-AS1 PTH2R LIMS1 MORN3 ESPNL DIDO1

C4orf48 CPS1 SCTR C12orf65

SH3RF3

SH3RF3-AS1 ZNF217

TRMT10A RUFY4 R3HDM1 PRH1-PRR4 SIX2 SPO11

NBLA00301 HAND2 OXTR ABCB6 CASC1 SIX2 SNAP25-AS1

RICTOR PEX5L HADHB DENND5B CDC42EP3 RBPJL

C5orf15 MSX2 AGBL5 PPHLN1 M1AP DBNDD2

LRRC4 GLP1R CAPG KCNC2 CASP10 FAM182B

PRRT4 FABP5 FARSB CRADD LOC541471 KCNB1

ELAVL2 ARSD COL4A4 KCTD10 STMN3 ACSS1

IDH3G CD160 SRBD1 TMEM233 SNAI1 PTGIS

TMEM9 FAM89A PCDP1 LTBR SAMD10 HELZ2

DUSP5P1 RHOU PIDD

MIR663B ANKRD30BL IKBIP ZBP1 LINC00176

CCDC7 TMPO HOXD9

CCDC169-

SOHLH2 SOHLH2 C20orf197 MIR1-1

SFXN4 DZIP1 USP37 MIPEPP3 TGIF2 NDRG3

MOB2 CHAMP1 ASXL2 LMO7 DNAJC5 KCNB1

ATM RHBDL3 CAPN13 SLITRK1 CST7 GTPBP5

SLC12A6 FLJ25758 HAAO TNFRSF19 LOC284798 UCKL1

RASL12 FXYD1 KCNK12 CDX2 LOC100506385 PCIF1

SSTR5 SSTR5-

AS1 PLA2G4C MYO1B

SUGT1P3

TPTE2P5

ITGB2 ITGB2-

AS1 SDCBP2-AS1 FKBP1A-SDCBP2

ENPP7 BTD FAM117B EBPL POFUT2 ASIP

ZNF461 NR1I2 COL4A3 PAN3-AS1 CDC42EP1 MYL9

CCDC74A LOC100506229 NDUFA10 DLEU7 CYTH4 SLC13A3

AMOTL2 PRSS35 RHOB DACH1 APOBEC3D MACROD2-AS1 MACROD2

SIAH2 MIR4478 FHL2 IFT88 ZNRF3-AS1 LINC00261

RNF4 MARC1

RNU6-81

LOC150776 KIAA1704 EFCAB6 SNAI1

FOXD1 KRTAP5-5 PLCL1 TFDP1 CCRL2 MIR155HG

PCDHB3 TRIM5 MOGAT1 RNASEH2B KCNMB2 CHODL

TFAP2A AP5B1 IQCA1 ITGBL1 GRK7 KRTAP21-1

DPYSL2 LPAR5 SPDYA CUL4A CMTM7 KCNE1

ADCK5 LAG3 HNRPLL RCBTB1 TGFBR2 AGPAT3

DMRT3 KRT6A FAM168B TPTE2P6 CNTN6 C21orf58

DNAI1 SELPLG ACVR1C LINC00598 ITIH4 APP

NFIL3 HVCN1 METAP1D PDS5B ZBBX ITGB2 ITGB2-AS1

SRSF4 COX16 TMEFF2 ADPRHL1 TNRC18P1 CECR5

SPAG6 VASH1 ARPC2 ATP7B HRH2 NCF4

H2AFY2 HSPB6 CNPPD1 SUCLA2 EGFLAM PKDREJ

AVPR1A SPO11 SPATA3 F10 ZNF366 LOC90834

FLJ31485 TTC28 AQP12B SLC25A15 RGS7BP UPB1 ADORA2A-AS1

RTN1 COLQ EML4 MEDAG

PCDHGB3 PCDHGB2

PCDHGA8

PCDHGA9 PCDHGC4

PCDHGB6

PCDHGB5 PCDHGB4

PCDHGA2

PCDHGA3 PCDHGA1

PCDHGA6

PCDHGA7 PCDHGA4

PCDHGA5 PCDHGA10

PCDHGA11

PCDHGA12 PCDHGC3

PCDHGB7

PCDHGB1 PCDHGC5 CELSR1

NAT9 HYAL2 SEMA4F GJB2 FGF1 CRKL

PLK5 FAM153B LRRTM1

CPB2 CPB2-

AS1 PP7080 FLJ46257

TMEM86B SYNJ2 ARHGEF4 SLC15A1

PCDHGB3

PCDHGB2

PCDHGA8 PCDHGC3

PCDHGB7 A4GALT

PCDHGB6 PCDHGB5

PCDHGB4

PCDHGA2 PCDHGA3

PCDHGA1

PCDHGA6 PCDHGA7

PCDHGA4

PCDHGA5 PCDHGA10

PCDHGA11

PCDHGA12 PCDHGA9

PCDHGC4

PCDHGB1 PCDHGC5

LINC00486 ENG NHEJ1 NALCN IRX4 NCAPH2

HOXD12 FBXW5 GBX2 RALGAPA1 SGCD LINC00634

ADRA1D HENMT1 EHD3 C14orf132 TRAF3IP2 NHP2L1 C22orf46

ZIC4 CAPN9 TGFA TCL1A MCUR1 EWSR1

CTNNAL1 PTGES3 FER1L5 MPP5 SCML4 MGAT3

C2CD2L TEX22 LOC100505695 C14orf180 FUCA2 ZNRF3-AS1

SPTLC2 CRIP2 C2orf83 SLC25A29 MGC39372 YDJC

CAMK2A CRK CHRND RCOR1 HIST1H4J AP1B1P1

PRRT4 TMEM221 ATXN7 KLHL33 LOC100652739 NCAPH2 SCO2

RGS3 PSG11 CD96 LINC00521 CREB3L2 C22orf23

TTF1 CMPK2 DCP1A STON2 STEAP1B TAB1

RPS6KA1 HHATL FSTL1 TCL1B SSPO GSC2

ZNF697 SPRY4 IP6K2 SYT16 LOC442497 HSCB

IFI16 UBR2 NUP210 CEP128 GIMAP8 NIPSNAP1

LRRN2 GFRAL IL17RE MIS18BP1

HOXA11-AS

HOXA11 LIMK2

DNAJB12 RASA4CP MAPKAPK3 NOVA1 EPDR1 TSSK2

SLC16A12 MIXL1 CCBP2 BAZ1A RFC2 RAC2

ASCL2 CDHR5 NEK4 ALDH6A1 LOC100506585 TUBA8

FKBP2 TTC12 SLC2A2 IRF2BPL ADCYAP1R1 GRAP2

SIPA1 JAM3 GOLGA4 SIX6 ABCB1 MEI1

JAM3 LRMP OSBPL10 SLC7A8 FLJ43663 RABL2B

HOXC4 RASD1 SIDT1 ABHD12B NFE2L3 ADORA2A-AS1

NXPH4 CCDC144NL H1FOO GSTZ1 ZKSCAN1 RRP7A

CLPX ARL5C RYK PAPOLA HR ZNF860

CD300LF SPATA20 LEKR1 SLC7A8 NSMCE2 TCTEX1D2

UNQ6975 MIR4785 GRIP2 PRKD1 TG SLA RHOA

IL12A UBASH3A KLHL24 KIAA0391 SPAG1 DRD3

SLC26A1 HHATL MAP3K13 ASB2 PPP1R42 SLC35G2

KCNQ5 PRSS45 IL1RAP TMEM179 ANXA13 BHLHE40

BVES ZMYND10 RAF1 PLEKHH1 GNAQ LMCD1-AS1

TNFSF8 GRIA1 UQCRC1 ELMSAN1 PTGS1 CCR5

TNFRSF1B LACE1 PRKCD CDH24

DKFZP434A062

GPSM1 FLJ25363

CASQ2

ISPD

LOC100506025 EIF4E3 GPR27 PRKCH GK SPSB4

CDH23 C10orf105 PGAM2 ATP2C1 C14orf159 FHL1 FETUB

LAG3 AEBP1 TRIM59 HHIPL1 RCC1 RAB5A

HOTAIR CLU BHLHE40-AS1 DHRS4L1 ZC3H12A DLG1

LOC400043 MUCL1 PRICKLE2-AS1 SIX1 HSPA6 SPATA16

DNMT3A MAFG LOC730091 EXD2 DARC STAB1

LOC728012 LINC00470 LRRC31 FBLN5 PDPN SHQ1

CHI3L1 VSIG10L

TMEM110

TMEM110-MUSTN1 SFTA3 MKNK1 LSAMP

C1QL3 POMC ZBTB11 PLEKHD1 CYMP PRR23A

LOC729683

LOC442028

TEKT4 COL6A6 XRCC3 YARS CRELD1

CD79B MIR3127 USP13 MIR548AI TRAF3IP3 ZNF620 MIR647

MIR1914 CBWD2 KAT2B ARHGAP5 WNT2B SEMA3G

SLC36A3 BBS7 WNT5A SPTSSA ARHGEF16 C3orf55

RSPH9 PLAG1 KIF9-AS1 ESR2 CNN3 LOC729970 KIF9

COG5 OR13J1 MIR1224 AHNAK2 LMOD1 ROBO2

TMEM65 TTLL10 PPARG FOXA1 ELTD1 ILDR1

NBPF3 SDE2 CAND2 FBXO34 ADAM30 SCAP

CERS2

FLJ39051

ST3GAL4 TPRA1 TMEM30B INPP5B ARIH2

PTPMT1 ITGA5 RBP1 MYO5C DHCR24 CEP70

LOC100132078 VRTN ACTL6A RHCG LINC00568 SCN11A

IL10RA NPHS1 MAP6D1

GATM GATM-

AS1 GPR161 HHLA2

MOB3A LINC00578 RARB C15orf56 PAK6 TNN EIF1B-AS1

ZNF208 PCDHGA6

OSBPL10

ZNF860 LOC283761 TNFRSF1B RTP2

MIR1914 NHS PTPN23 DLL4 LEPR PIGZ

LINC00114 BARHL2 ABHD14B C15orf52 NUP210L ZNF589

ABHD14A-

ACY1 ABHD14A SERPINA12 NEK4 STRA6 C1orf204 MIR548A2 ADAMTS9-AS2

WDR82 S1PR4 ANKRD18DP CA12 PRDX1 SLC25A26

CCDC96 LOC285000 PRRT3-AS1 LOXL1 IL12RB2 PDIA5

RGAG4 AGBL3 TAGLN3

LOXL1

LOXL1-AS1 SLC9C2 EGFEM1P

MDK INSRR NTRK1 NMD3 MEX3B ARL8A VWA5B2 CLCF1

LOC100130987 C17orf62 THRB TCF12 KCNK2 KIAA0226

ZNF385A RBBP8NL SLMAP MAP2K5 KMO MON1A

PROCA1 LOC100009676 FOXP1 RBPMS2 CDC42 MORC1

IL17RA LOC100128750 PRRT3 NEO1 EIF2B3 LMLN

PRR23A STAU2-AS1 CCDC51 BNC1 TRIM45 SUCLG2

FLJ34208 ACTL7A PFKFB4 IQGAP1 LCE3A SLITRK3

S100P DIAPH2 BSN LRRC28 FAM189B GPR160

CCDC152 LOC100288637 EIF4E3 GABRG3 SFPQ CLDN11

MAK IZUMO1 SLC41A3 HERC2 FAM78B ARPC4-TTLL3 ARPC4 MRVI1-AS1

LYVE1 CHRND CLSTN2 CATSPER2 GPA33 CAND2

CIZ1 LINC00189 ABCC5 LINC00277 MIR548H4 LOC100506023 MAP4

KAZN

TMEM51-AS1 TSPAN33

SLC6A1

SLC6A1-AS1 ISL2 CEP350 RBM15B

FOXD4L1 MYO5C ENTPD3-AS1 C15orf40 PLA2G5 RAD54L2

TMEM37 MGAT3 FAM86DP SPINT1 CD58 PDZRN3

IGFBP5 TBX5-AS1 NDUFAF3 ANXA2 LOC401980 PPP2R3A

LOC90834 IQCA1 FEZF2 NEIL1 SYNC CMTM7

MUC20 EREG GATA2 RASGRP1 DNTTIP2 TOPAZ1

MDFI CCDC152 WWTR1 DUOX1 ZNF648 CSPG5

CBX5 SLC16A2 GP5 SNX33 B3GALT6 PPP4R2

DSCR9 NPY1R ZCWPW2 SNRPA1 C1orf200 ZKSCAN7

VPS37D

Supplemental data S2.

GO analysis on PN/NN comparison with SAG

GO biological process complete Fold Enrichment P-value

establishment of skin barrier (GO:0061436) 39.66 4.16E-07

DNA integration (GO:0015074) 37.58 6.34E-07

regulation of water loss via skin (GO:0033561) 35.70 9.47E-07

RNA-dependent DNA biosynthetic process (GO:0006278) 23.62 2.36E-06

regulation of keratinocyte proliferation (GO:0010837) 17.27 1.41E-02

proximal/distal pattern formation (GO:0009954) 16.23 2.01E-02

multicellular organismal water homeostasis (GO:0050891) 14.87 1.96E-05

water homeostasis (GO:0030104) 12.39 1.08E-04

cornification (GO:0070268) 11.36 4.02E-07

regulation of epidermis development (GO:0045682) 10.82 8.57E-03

skin epidermis development (GO:0098773) 9.27 2.65E-02

skin development (GO:0043588) 8.35 1.01E-17

keratinocyte differentiation (GO:0030216) 7.99 8.44E-11

epidermis development (GO:0008544) 7.86 1.84E-17

regulation of epithelial cell differentiation (GO:0030856) 7.26 1.39E-02

epidermal cell differentiation (GO:0009913) 6.91 1.85E-09

keratinization (GO:0031424) 6.37 6.37E-05

cell junction organization (GO:0034330) 5.64 1.74E-02

urogenital system development (GO:0001655) 4.96 7.87E-04

epithelial cell differentiation (GO:0030855) 4.78 2.24E-10

regulation of epithelial cell proliferation (GO:0050678) 4.73 3.53E-03

morphogenesis of an epithelium (GO:0002009) 4.27 6.29E-04

epithelium development (GO:0060429) 4.19 5.62E-14

gland development (GO:0048732) 4.16 2.02E-03

regulation of body fluid levels (GO:0050878) 4.16 1.04E-04

tissue development (GO:0009888) 4.13 7.36E-24

tissue morphogenesis (GO:0048729) 3.94 2.73E-04

negative regulation of cell proliferation (GO:0008285) 3.49 6.68E-04

embryonic morphogenesis (GO:0048598) 3.38 1.26E-02

anatomical structure formation involved in morphogenesis (GO:0048646) 3.38 3.40E-05

response to wounding (GO:0009611) 3.24 4.26E-02

regulation of cellular component movement (GO:0051270) 3.21 3.41E-04

animal organ morphogenesis (GO:0009887) 3.16 1.62E-04

regulation of cell migration (GO:0030334) 3.10 1.00E-02

regulation of cell adhesion (GO:0030155) 3.05 3.61E-02

regulation of cell motility (GO:2000145) 3.01 9.96E-03

positive regulation of cell differentiation (GO:0045597) 2.96 3.04E-03

cell adhesion (GO:0007155) 2.91 8.13E-05

biological adhesion (GO:0022610) 2.90 9.12E-05

regulation of locomotion (GO:0040012) 2.89 1.30E-02

cell death (GO:0008219) 2.86 3.41E-04

positive regulation of developmental process (GO:0051094) 2.80 1.36E-04

programmed cell death (GO:0012501) 2.79 1.53E-03

regulation of cell proliferation (GO:0042127) 2.79 7.83E-07

cellular response to oxygen-containing compound (GO:1901701) 2.77 2.69E-02

anatomical structure morphogenesis (GO:0009653) 2.73 3.90E-09

regulation of cell differentiation (GO:0045595) 2.67 7.96E-06

response to abiotic stimulus (GO:0009628) 2.66 4.32E-03

positive regulation of multicellular organismal process (GO:0051240) 2.63 7.58E-05

cellular response to endogenous stimulus (GO:0071495) 2.62 1.40E-02

embryo development (GO:0009790) 2.62 4.92E-02

animal organ development (GO:0048513) 2.56 2.35E-13

response to endogenous stimulus (GO:0009719) 2.39 6.97E-03

regulation of multicellular organismal development (GO:2000026) 2.34 6.22E-04

cell differentiation (GO:0030154) 2.32 1.48E-11

response to oxygen-containing compound (GO:1901700) 2.31 2.03E-02

cellular developmental process (GO:0048869) 2.29 1.80E-11

regulation of developmental process (GO:0050793) 2.29 1.14E-05

system development (GO:0048731) 2.26 3.41E-14

cell development (GO:0048468) 2.24 3.14E-02

regulation of multicellular organismal process (GO:0051239) 2.22 2.00E-06

multicellular organism development (GO:0007275) 2.21 5.90E-16

anatomical structure development (GO:0048856) 2.17 1.04E-16

developmental process (GO:0032502) 2.10 2.54E-16

single-multicellular organism process (GO:0044707) 2.07 4.40E-16

single-organism developmental process (GO:0044767) 2.06 7.66E-15

regulation of localization (GO:0032879) 1.94 1.07E-02

negative regulation of cellular process (GO:0048523) 1.85 8.21E-06

regulation of cell communication (GO:0010646) 1.84 6.12E-03

positive regulation of cellular process (GO:0048522) 1.82 1.99E-06

regulation of signaling (GO:0023051) 1.81 1.08E-02

positive regulation of biological process (GO:0048518) 1.80 2.05E-07

negative regulation of biological process (GO:0048519) 1.79 1.48E-05

multicellular organismal process (GO:0032501) 1.75 6.80E-10

regulation of response to stimulus (GO:0048583) 1.69 2.84E-02

signal transduction (GO:0007165) 1.67 6.24E-04

single organism signaling (GO:0044700) 1.61 1.48E-03

signaling (GO:0023052) 1.61 1.54E-03

cell communication (GO:0007154) 1.60 1.65E-03

cellular response to stimulus (GO:0051716) 1.50 8.31E-03

single-organism cellular process (GO:0044763) 1.46 2.72E-07

regulation of cellular process (GO:0050794) 1.36 1.31E-04

regulation of biological process (GO:0050789) 1.33 5.08E-04

single-organism process (GO:0044699) 1.30 2.29E-05

biological regulation (GO:0065007) 1.29 3.71E-03

cellular process (GO:0009987) 1.21 3.12E-04

biological_process (GO:0008150) 1.13 1.55E-02

Supplemental data S3.

GO analysis on PP/NN comparison with SAG

GO biological process complete Fold Enrichment P-value

desmosome organization (GO:0002934) 30.22 7.19E-03

keratinocyte proliferation (GO:0043616) 25.18 1.74E-02

establishment of skin barrier (GO:0061436) 23.50 2.47E-04

regulation of water loss via skin (GO:0033561) 21.15 5.01E-04

regulation of keratinocyte proliferation (GO:0010837) 19.50 1.59E-06

epidermis morphogenesis (GO:0048730) 14.10 7.44E-03

cornification (GO:0070268) 13.19 2.01E-15

proximal/distal pattern formation (GO:0009954) 12.82 1.39E-02

intermediate filament cytoskeleton organization (GO:0045104) 12.09 3.89E-03

intermediate filament-based process (GO:0045103) 11.79 4.68E-03

skin epidermis development (GO:0098773) 11.77 5.57E-08

hair follicle development (GO:0001942) 11.28 4.88E-07

hair cycle process (GO:0022405) 10.85 8.08E-07

molting cycle process (GO:0022404) 10.85 8.08E-07

multicellular organismal water homeostasis (GO:0050891) 10.07 7.69E-04

hair cycle (GO:0042633) 9.85 6.44E-07

molting cycle (GO:0042303) 9.85 6.44E-07

skin development (GO:0043588) 9.37 1.10E-33

epidermis development (GO:0008544) 9.31 8.67E-37

epithelial cell proliferation (GO:0050673) 9.14 2.89E-05

keratinocyte differentiation (GO:0030216) 9.02 1.55E-21

water homeostasis (GO:0030104) 8.39 4.00E-03

regulation of epidermis development (GO:0045682) 8.24 1.73E-02

epidermal cell differentiation (GO:0009913) 7.99 3.19E-20

keratinization (GO:0031424) 7.28 2.25E-11

response to cAMP (GO:0051591) 6.72 9.37E-03

regulation of fat cell differentiation (GO:0045598) 5.94 3.01E-02

formation of primary germ layer (GO:0001704) 5.94 3.01E-02

regulation of epithelial cell differentiation (GO:0030856) 5.90 1.17E-02

response to glucocorticoid (GO:0051384) 5.57 7.95E-03

response to corticosteroid (GO:0031960) 5.39 4.51E-03

regulation of response to wounding (GO:1903034) 5.38 1.16E-02

epithelial cell differentiation (GO:0030855) 5.18 1.04E-19

cellular response to acid chemical (GO:0071229) 4.96 2.11E-03

regulation of epithelial cell proliferation (GO:0050678) 4.80 3.91E-06

cell junction organization (GO:0034330) 4.77 8.01E-03

epithelium development (GO:0060429) 4.65 9.92E-28

epithelial cell development (GO:0002064) 4.65 2.47E-02

morphogenesis of an epithelium (GO:0002009) 4.34 2.85E-07

tissue development (GO:0009888) 4.18 2.91E-37

urogenital system development (GO:0001655) 4.15 5.69E-04

response to acid chemical (GO:0001101) 4.05 4.10E-04

tissue morphogenesis (GO:0048729) 3.94 1.65E-07

renal system development (GO:0072001) 3.76 3.65E-02

regulation of lipid metabolic process (GO:0019216) 3.73 2.20E-02

multicellular organismal homeostasis (GO:0048871) 3.68 4.84E-02

regulation of Wnt signaling pathway (GO:0030111) 3.65 1.59E-02

cell-cell signaling by wnt (GO:0198738) 3.60 5.69E-03

Wnt signaling pathway (GO:0016055) 3.60 5.69E-03

response to metal ion (GO:0010038) 3.51 4.94E-02

regulation of body fluid levels (GO:0050878) 3.43 2.09E-04

gland development (GO:0048732) 3.41 4.18E-03

response to peptide (GO:1901652) 3.28 1.35E-02

reproductive structure development (GO:0048608) 3.24 1.70E-02

cellular response to organonitrogen compound (GO:0071417) 3.22 6.21E-03

reproductive system development (GO:0061458) 3.20 2.06E-02

embryonic morphogenesis (GO:0048598) 3.16 6.26E-04

response to organonitrogen compound (GO:0010243) 3.11 5.00E-06 cell surface receptor signaling pathway involved in cell-cell signaling (GO:1905114) 3.11 3.23E-02

response to inorganic substance (GO:0010035) 3.09 2.13E-02

cellular response to oxygen-containing compound (GO:1901701) 3.03 2.17E-06

cellular response to growth factor stimulus (GO:0071363) 3.03 2.94E-02

negative regulation of cell proliferation (GO:0008285) 3.03 3.52E-04

tube development (GO:0035295) 3.01 2.82E-03

positive regulation of cell differentiation (GO:0045597) 3.01 2.78E-06

wound healing (GO:0042060) 2.99 3.63E-02

response to growth factor (GO:0070848) 2.98 2.30E-02

cell death (GO:0008219) 2.96 2.94E-08

response to wounding (GO:0009611) 2.96 6.29E-03

cell-cell adhesion (GO:0098609) 2.93 4.42E-04

regulation of cellular component movement (GO:0051270) 2.92 2.70E-05

cellular response to endogenous stimulus (GO:0071495) 2.90 2.84E-07

programmed cell death (GO:0012501) 2.89 2.94E-07

anatomical structure formation involved in morphogenesis (GO:0048646) 2.88 4.03E-05

cellular response to nitrogen compound (GO:1901699) 2.87 2.76E-02

regulation of cell proliferation (GO:0042127) 2.83 8.81E-12

animal organ morphogenesis (GO:0009887) 2.83 2.65E-05

response to nitrogen compound (GO:1901698) 2.81 5.14E-05

regulation of cell migration (GO:0030334) 2.80 1.99E-03

cell adhesion (GO:0007155) 2.79 3.86E-07

regulation of cell projection organization (GO:0031344) 2.78 1.97E-02

biological adhesion (GO:0022610) 2.78 4.52E-07

regulation of cell motility (GO:2000145) 2.77 1.02E-03

response to hormone (GO:0009725) 2.77 6.80E-04

positive regulation of developmental process (GO:0051094) 2.77 1.36E-07

response to lipid (GO:0033993) 2.74 3.77E-04

response to endogenous stimulus (GO:0009719) 2.71 8.07E-09

embryo development (GO:0009790) 2.69 1.07E-04

regulation of cell differentiation (GO:0045595) 2.67 9.36E-10

regulation of cell adhesion (GO:0030155) 2.63 3.67E-02

regulation of locomotion (GO:0040012) 2.63 2.24E-03

response to oxygen-containing compound (GO:1901700) 2.61 8.79E-08

regulation of neurogenesis (GO:0050767) 2.61 1.91E-02

anatomical structure morphogenesis (GO:0009653) 2.59 3.14E-12

animal organ development (GO:0048513) 2.55 1.63E-20

regulation of nervous system development (GO:0051960) 2.55 9.81E-03

regulation of response to external stimulus (GO:0032101) 2.55 3.15E-02

negative regulation of signal transduction (GO:0009968) 2.42 6.23E-04

negative regulation of response to stimulus (GO:0048585) 2.40 1.54E-05

negative regulation of cell communication (GO:0010648) 2.38 3.43E-04

response to organic cyclic compound (GO:0014070) 2.38 3.03E-02

negative regulation of signaling (GO:0023057) 2.37 3.79E-04

response to abiotic stimulus (GO:0009628) 2.31 5.95E-03

cellular response to organic substance (GO:0071310) 2.30 1.22E-07

cell differentiation (GO:0030154) 2.26 1.81E-16

positive regulation of multicellular organismal process (GO:0051240) 2.25 2.74E-04

cellular response to chemical stimulus (GO:0070887) 2.24 3.32E-09

cellular developmental process (GO:0048869) 2.23 3.97E-16

regulation of developmental process (GO:0050793) 2.22 2.39E-08

system development (GO:0048731) 2.19 1.80E-19

regulation of multicellular organismal development (GO:2000026) 2.15 1.05E-04

multicellular organism development (GO:0007275) 2.13 1.25E-21

anatomical structure development (GO:0048856) 2.11 2.73E-23

cell development (GO:0048468) 2.09 4.77E-03

response to organic substance (GO:0010033) 2.08 1.30E-07

developmental process (GO:0032502) 2.07 7.80E-24

single-organism developmental process (GO:0044767) 2.05 3.69E-22

single-multicellular organism process (GO:0044707) 2.03 9.73E-23

regulation of localization (GO:0032879) 2.02 2.59E-06

regulation of multicellular organismal process (GO:0051239) 2.00 9.37E-07

regulation of programmed cell death (GO:0043067) 2.00 4.46E-02

neurogenesis (GO:0022008) 1.99 3.04E-02

response to external stimulus (GO:0009605) 1.92 1.79E-02

cell surface receptor signaling pathway (GO:0007166) 1.91 7.55E-04

regulation of cell communication (GO:0010646) 1.82 3.92E-05

positive regulation of cellular process (GO:0048522) 1.82 1.10E-10

nervous system development (GO:0007399) 1.81 1.27E-02

regulation of signaling (GO:0023051) 1.81 4.16E-05

regulation of signal transduction (GO:0009966) 1.80 6.10E-04

negative regulation of biological process (GO:0048519) 1.78 5.27E-09

positive regulation of macromolecule metabolic process (GO:0010604) 1.77 1.16E-03

regulation of cellular protein metabolic process (GO:0032268) 1.76 1.79E-02

positive regulation of cellular metabolic process (GO:0031325) 1.76 1.23E-03

negative regulation of cellular process (GO:0048523) 1.76 1.51E-07

positive regulation of metabolic process (GO:0009893) 1.75 5.74E-04

multicellular organismal process (GO:0032501) 1.75 6.43E-16

regulation of biological quality (GO:0065008) 1.73 6.14E-05

regulation of protein metabolic process (GO:0051246) 1.71 3.02E-02

positive regulation of biological process (GO:0048518) 1.71 3.10E-09

regulation of molecular function (GO:0065009) 1.68 1.22E-02

response to chemical (GO:0042221) 1.67 1.64E-04

regulation of response to stimulus (GO:0048583) 1.67 4.30E-04

response to stress (GO:0006950) 1.65 7.29E-03

cell communication (GO:0007154) 1.60 2.19E-06

signal transduction (GO:0007165) 1.60 2.96E-05

single organism signaling (GO:0044700) 1.56 4.32E-05

signaling (GO:0023052) 1.56 4.54E-05

cellular response to stimulus (GO:0051716) 1.54 2.72E-06

regulation of primary metabolic process (GO:0080090) 1.48 6.47E-04

regulation of macromolecule metabolic process (GO:0060255) 1.48 6.61E-04

regulation of cellular metabolic process (GO:0031323) 1.47 9.44E-04

regulation of metabolic process (GO:0019222) 1.46 4.92E-04

single-organism cellular process (GO:0044763) 1.43 2.82E-10

response to stimulus (GO:0050896) 1.41 4.39E-05

regulation of cellular process (GO:0050794) 1.35 2.36E-07

single-organism process (GO:0044699) 1.32 2.31E-10

biological regulation (GO:0065007) 1.31 3.31E-07

regulation of biological process (GO:0050789) 1.31 6.26E-06

cellular process (GO:0009987) 1.20 8.88E-06

biological_process (GO:0008150) 1.12 3.91E-04

Supplemental data S4.

Psoriasis risk-associated genes

SLC45A1 NFKBIA IL28RA PRM3 RUNX3 PRSS53 IL23R NOS2 LRRC7 PTRF LCE3B CARD14 FLJ16341 POL1 B3GNT2 TYK2 KCNH7 ILF3 PLCL2 RNF114 NFKBIZ UBE2L3 PTGER4 CARD6 ERAP1 AKAP13 IL13 FUBP1 TNIP1 FASLG IL12B IKBKE EXOC2 ZNF365 HLA‐B PTEN TRAF3IP2 CHUK TNFAIP3 CFL1 TAGAP KLRK1 ELMO1 BRAP DDX58 IL31 KLF4 UBAC2 CAMK2G RP11-61O1.1

ZMIZ1 KLF13 RPS6KA4 TRIM47 ZC3H12C PTPN2 ETS1 FUT2 STAT2

Figure 1

b

c

a

100% 50% 0% 50% 100%

-log1

0 p-

valu

e0

5

10

1

5

hypomethylation hypermethylation

Hypermethylated sites Hypomethylated sites

PP PN PP PN PP NNPP NN

PN NN PN NN

Figure 2

a

b

Psoriasis involved 1

Psoriasis involved 2

Psoriasis involved 3

Psoriasis uninvolved 1

Psoriasis uninvolved 2

Psoriasis uninvolved 3

Control 1

Control 2

Control 3

Control 4

Control 5

Control 6

Psoriasis involved 1 Psoriasis involved 2 Psoriasis involved 3 Psoriasis uninvolved 1 Control 1 Control 2 Control 3 Psoriasis uninvolved 3 Psoriasis uninvolved 2