control of gene expression ( 유전자 발현의 조절 ) chapter 16
TRANSCRIPT
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 .