Control of Gene Expression( 유전자 발현의 조절 )

Chapter 16

염색질 재조정 단백질 ( 금색 ) 이 염색질 ( 청색 ) 에 붙음 .

그림 16.1. 사람의 난자가 난소에서 배란되는 순간

16.1 Regulation of Gene Expression in Prokaryotes

Operon is the unit of transcription in prokaryotes

lac operon for lactose metabolism ( 젖당 대사 )is transcribed when an inducer ( 유도자 ) inactivates a repressor ( 억제자 )

Transcription of trp operon genes is repressed when tryptophan activates a repressor

Transcription of the lac operon is also controlled by a positive regulatory system ( 양성조절체계 )

Gene Expression Control

All somatic cells in an organism are genetically identical• Cells differentiate by gene expression

Gene expression is collectively controlled through transcriptional regulation• Main control: Gene transcribed into mRNA

• Additional controls: Posttranscriptional, translational and posttranslational

Operon: Unit of Transcription (1)

Prokaryotic gene expression reflects life history• Rapid, reversable response to environment

Operon: A cluster of prokaryotic genes and DNA sequences involved in their regulation• RNA polymerase binds at promoter for operon

• Many genes may be transcribed into one mRNA

• Cluster of genes is transscriptional unit

Operon: Unit of Transcription (2)

Regulatory proteins bind at operator• Regulatory protein coded by gene outside operon

Repressor proteins prevent operon genes from being expressed

Activator proteins turn on expression of genes from operon

lac Operon for Lactose Metabolism

Lactose metabolism in E. coli requires three genes lacZ, lacY and lacA• lac operon contains all three genes and

regulatory sequences

lac operon operator sequence is between promoter and lacZ

그림 16.2. 대장균의 lac 오페론 .

lac Operon for Lactose Metabolism

lac repressor stops lac operon expression• Encoded by lacI, synthesized in active form• Binds promoter, prevents transcription

Allolactose made from lactose when it enters cell, lasts as long as lactose available• Inducer of lac operon by binding to lac repressor• Inducible operon because inducer increases

expression

그림 16.3. 젖당이 없는 조건 (a), 있는 조건 (b)에서의 Lac 억제자에 의한 inducible lac 오페론의 조절 .

trp Operon Genes

Tryptophan amino acid needed for protein synthesis• Energy efficient, to use when available

• If unavailable, E. coli must make it

Five genes, trpA-trpE needed for synthesis of tryptophan by trp operon• trp repressor encoded by trpR elsewhere in

genome

• trp respressor synthesized in inactive form

trp Operon Regulation

Default state of trp operon is expression since Trp repressor is inactive• Trp repressor activiated by presence of

tryptophan

trp Operon is repressible operon• Tryptophan is corepressor

lac and trp operons both exhibit negative gene regulation

그림 16.4. 트립토판이 없는 조건(a), 있는 조건 (b) 에서 Trp 억제자에 의한 repressible trp오페론의 조절 .

Positive Regulation of lac Operon

lac operon operates when lactose but not glucose is present • Glucose more efficient energy source than

lactose

Catabolite Activator Protein (CAP) is an activator that stimulates gene expression• CAP activated by cAMP • cAMP only abundant when glucose levels are low

그림 16.5. CAP 활성자에 의한 lac 오페론의 positive regulation.

16.2 Regulation of Transcription in Eukaryotes

In eukaryotes, regulation of gene expression occurs at several levels

Chromatin structure plays an important role in whether a gene is active or inactive

Regulation of transcription initiation involves a gene’s promoter and regulatory sites

Methylation of DNA can control gene transcription

Regulation of Gene Expression in Eukaryotes

Gene expression in eukaryotes has more regulatory points• Chromatin has histones• Different types of cells• Nuclear envelope

Three main areas of eukaryotic regulation of gene expression• Transcriptional, posttranscriptional and

posttranslational

그림 16.6. 진핵생물에서의 전사 시 , 전사 후 , 번역 시 , 번역 후 유전자 발현 조절의 단계들 .

Chromatin Structure

Eukaryotic DNA wraps around histones, is further structured into nucleosomes• Promoters inaccessible

Chromatin remodeling ( 염색질 재조정 ) makes gene promoters more accessible• Activators recruit remodeling complexes that

displace nucleosomes• Activators recruit enzyme that acetylates and

loosens histone assocation with DNA

그림 16.7. 염색체 재조정에 의한 유전자 프로모터의 노출 .

Transcription Initiation Regulation

Eukaryotic gene organization allows regulation• Promoter includes TATA box that binds

transcription factors• Promoter proximal region ( 프로모터 근접 구역 ) upstream of promoter increases transcription rates

• Enhancer ( 증폭자 ) further upstream determines maximum transcription rate

그림 16.8. 진핵생물의 유전자 구조 .

Transcription Initiation Regulation

General transcription factors initiate transcription• Bind to TATA box area and recruit RNA

polymerase II• Transcriptional initiation complex (전사개시복합체 ), low rate

Activators bind to promoter proximal elements and increase transcription rate

그림 16.9. 프로모터에서 일반전사인자들과 RNA 중합효소가 전사복합체를 형성 .

Transcription Initiation Regulation

Coactivators ( 보조활성자 ) bridge enhancer and promoter• Protein interactions and RNA polymerase

increase transcription

Repressors oppose effect of activators• Transcription rate depends on activation and

repression signals• May bind to sites of activator or coactivator or

increase association with histones

그림 16.10. 증폭자에서의 활성자 및 보조활성자들과 프로모터에 있는 일반전사인자들 사이의 상호작용에 의해 전사가 최대속도로 일어남 .

Transcription Initiation Regulation

Combinatorial regulation allow genes with related functions to respond to one signal

Hormones • Signal molecules produced in one tissue and

transported to another• Activate all cells with specific hormone receptors

그림 16.11. 조합적 유전자 발현 조절 .

그림 16.12. 스테로이드 호르몬에 의한 유전자 발현 조절 .

Methylation of DNA

DNA methylation adds –CH3 to cytosine

• Gene silencing occurs when DNA methylation is located in promoters

• Example: Barr bodies

Genomic imprinting ( 유전체 각인 )• Permanent silencing of a maternal or paternal

allele• Inherited methylated allele is silenced• Methylation maintained as DNA is replicated

16.3 Posttranscriptional, Translational, and Posttranslational Regulation

Posttranscriptional regulation ( 전사 후 조절 ) controls mRNA availability

Translational regulation ( 번역 시 조절 ) controls the rate of protein synthesis

Posttranslational regulation ( 번역 후 조절 ) controls the availability of functional proteins

Posttranscriptional Regulation

Posttranscriptional regulation controls availability of mRNA to ribosomes

Pre-mRNA processing changes which proteins are made• Alternative splicing of introns and exons• Eukaryotic evolutionary advantage

Posttranscriptional Regulation

Masking proteins bind to mRNA to prevent translation• Signal for mRNA activation removes masking

proteins during development

mRNA breakdown rates are variable• Mechanism: 5’ UTR nucleotide sequences

Posttranscriptional Regulation

Micro-RNA (miRNA) regulates gene expression through RNA interferance (RNAi)• miRNA binds to any complementary mRNA

sequence and silences it

Small interfering RNA (siRNA) is from RNA encoded outside the cell’s genome• Often used by viruses

• Gene therapy implications

그림 16.13. RNAi-miRNA 에 의한 유전자 발현의 조절 .

Translational and Posttranslational Regulation

Translational regulation controls mRNA translation by ribosomes• Increasing length of poly(A) tail increases

translation of mRNA

Posttranslational regulation controls functional proteins• Chemical modification alters activity of protein

• Processes inactive precursers to active proteins

• Example: Rate of degradation, ubiquitin

그림 16.14. 유비퀴틴 추가에 의한 분해될 단백질의 표식과 프로테아좀 내에서의 효소 작용에 의한 분해

16.4 Loss of Regulatory Controls in Cancer

Most cancers are caused by genes that have lost their normal controls

Cancer develops gradually by multiple steps

Cancer and Gene Controls

Tumor: A mass of cells due to dedifferentation ( 탈분화 )• Benign tumors single mass

• Malignant tumors (cancer) invade other tissues by metastasis ( 전이 )

• Tumor-repressor gene function lost

Proto-oncogens ( 원발암유전자 ) encode proteins that stimulate cell division• Oncogenes altered proto-oncogenes that cause a

cell to be cancerous

그림 16.15. 백혈구들로 싸인 암세포의 전자현미경 사진 .

Mechanisms of Oncogene Formation

Mutations in promoter or control sequences

Mutations in coding segment may produce abnormally active protein

Segment of chromosome translocated to area near promoter or enhancer

Viral infection of gene that regulates cell cycle

Cancer Develops Gradually

Multiple genes must be modified to develop cancer• Explains why carcinogens may cause cancer

years later

• Removal of carcinogen may halt multistep progression oncogenes

그림 16.16. 특정 직장암의 발달에 관한 다단계 모형 .