Epigenetic and Expression Regulation -.ppt
May 26, 2016 | Author: Susi Rutmalem | Category: N/A
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Epigenetic and Expression Regulation Sofia Mubarika
DNA
RNA
PROTEIN
Genome : 40.000 genes Transcriptome > 100.000 RNA Proteome > 400.000 proteins Variability : genomic variations Gene expression, alternative splicing Protein cleavage,modification
Central Dogma DNA Translation
RNA Transcription A gene is expressed in 3 steps:
Protein
1) Transcription: RNA synthesis 2) Splicing: removal of intron sequence from RNA 3) Translation: Protein synthesis
Central Dogma
DNA
Genotype RNA function & structure Protein sequence
RNA
Protein structure
Protein
Protein Function Phenotype
Gene Regulatory Mechanisms
Transcriptional Mechanisms Type of promoters & RNA polymerase Control of Transcription Constitutive Inducible Repressible Transcription Factors and TFBS Translational Mechanisms Micro RNAs (miRNAs and RITS complexes) Translational control mRNA degradation Promoter activation Silencer RNAs (siRNAs & RISC complexes) degrading mRNA Epigenetic Mechanisms Chromatin remodeling Histone modifications (acetylation, phosphorylation, methylation …) DNA methylation
Epigenetics ?? Epigenetics is:
Genome DNA
Reversible changes in gene expression Without
changes in DNA sequence
Can
be inherited from precursor cells
Epigenetic information is included in the epigenome
Chromatin
Epigenome
Gene Expression
Phenotype
Chromatin – Key Component of Epigenetic Mechanisms Cellular DNA is packaged into a structure called chromatin The unit of chromatin is the nucleosome, a complex of a histone tetramer with approx. 125 bp of DNA wound around it nucleosome
histone DNA
chromatin
Chromatin organizes genes to be accessible for transcription, replication, and repair
DNA Methylation can Prevent Gene Expression DNMT
TF
DNMT TF
Ac
Ac
Ac
Ac Ac
Gene expression
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Ac
Ac
Ac Ac Ac
DNMT
Ac
Me
Me Ac
Me
DNMT Me
Me Ac
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Me Ac
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Gene expression
DNA methylation involves the transfer of methyl groups to cytosine residues in DNA by DNA methyltransferases (DNMTs)
May prevent transcription factors from binding to DNA
May serve as binding site for methylated DNA-binding proteins, such as MECP2, which then recruit HDACs
Me
Histone Methylation can Affect Chromatin Structure Me
HDAC HMT
Me
Me Me
Ac
Ac
Me
Me
Me
HMT HDAC
Ac
Me
Me
Gene expression
Me
Gene expression
Histone methylation by histone methyltransferases (HMTs) can recruit HDACs, leading to: Closed chromatin structure Gene silencing
Other Epigenetic Modifications of Histones and DNA Histone Methylation
Histone Acetylation Ac
Me Me Me
DNA Methylation
Epigenetic Modifications to Histones and DNA Can Cooperate to Silence Gene Expression DNMT
DNMT
HDAC
Ac Ac Ac
Ac
Ac
Ac Ac
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Ac Ac
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HDAC
TF Me Me
Me Me
Me
Me
•
Me
Gene expression
Epigenetic modifications can cooperate to silence gene expression
Imbalanced Levels of Histone Acetylation Deregulate Gene Expression HAT
HISTONE ACETYLATION
TF Ac
Ac Ac
TF
Deacetylated Histones Closed chromatin Transcription factors cannot access DNA
HISTONE DEACETYLATION
HDAC
Ac
Ac Ac
Ac Ac
Ac
Acetylated Histones Open chromatin Transcription factors can access DNA
Increased HDAC activity or decreased HAT activity may result in aberrant gene expression, contributing to cancer
Epigenetics Play Important Roles in Normal Cellular Development and in Cancer EPIGENETICS
Normal epigenetic mechanisms
Normal differentiated cells, e.g. embryonic cells, hematopoetic cells
Deregulated epigenetic mechanisms
Malignant progenitor cell
Tumor
Epigenetic mechanisms can regulate genes involved in differentiation, cell cycle, and cell survival
Deregulation of epigenetic mechanisms results in aberrant gene expression, which can lead to cancer
Reversal of deregulated epigenetic changes is a rational strategy for targeting cancer
Historically, Cancer Was Considered to be Driven Mostly by Genetic Changes GENETIC
Example: Replication errors X X
Altered DNA sequence Altered DNA/mRNA/proteins
Oncogenesis
Tumor
Epigenetic Changes Important in Causing Cancer GENETIC
EPIGENETIC
Example: Chromatin modification errors
Example: Replication errors X X
Altered chromatin structure
Altered DNA sequence Altered DNA/mRNA/proteins
Oncogenesis
Tumor
Altered levels of miRNA/proteins
Cancer epigenetics
Epigenetic alterations found in almost all types of cancers 50% of genes that cause familial forms of cancer are found silenced in sporadic forms of cancer Large number of epigenetic alterations found in cancer cells due to: Stochastic occurrences that accumulate with age, selected for during tumour formation Caused by defects in components of the epigenetic machinery Repair gene (repair defects) alterations
Cancer epigenetics
Changes in 5-me-C distribution in DNA Hypermethylation of promoter CpG islands (found in ~50% genes) associated with TSGs Decreased expression levels/silencing of TSGs Increased mutations Global hypomethylation Chromosome instability (particularly pericentromeric repeats) Activation of viruses Activation of proto-oncogene Changes in chromatin structure Histone modifications: Histone deacetylation Histone methylation (H3-K9); demethylation (H3-K4) Histone sumoylation Heterochromatin-associated proteins
Epigenetics & Genetic Mutations Can Cooperate to Promote Oncogenesis GENETIC
EPIGENETIC
Oncogene function
Oncogene levels
↓ Tumor suppressor function
↓ Tumor suppressor levels Oncogenesis
Tumor
Epigenetics Play Important Roles in Normal & Cancer Development EPIGENETICS
Normal epigenetic mechanisms
Normal differentiated cells, e.g. embryonic cells, hematopoetic cells
Deregulated epigenetic mechanisms
Malignant progenitor cell
Tumor
Epigenetic mechanisms can regulate genes involved in differentiation, cell cycle, and cell survival
Deregulation of epigenetic mechanisms results in aberrant gene expression, which can lead to cancer
Reversal of deregulated epigenetic changes is a rational strategy for targeting cancer
Cancer Stem Cell Theory: the ‘Root’ of Cancer Growth
Tumor
Tumor Development and Growth Epigenetically altered, self-renewing cancer stem cells
Conventional Therapies May Target Tumor Cells, Not Cancer Stem Cells Conventional therapy
Target tumor
Cancer stem cells survive
Tumor regrowth
Epigenetic Therapy May Target Cancer Stem Cells and Tumor Cells Epigenetic therapy
Target tumor and cancer stem cells
Tumor and cancer stem cell death
No regrowth
Section 1: Importance of Epigenetics in Cancer
Section 2: Mechanisms of Epigenetics: Focus on Deacetylation
Section 3: Therapeutic Targeting of Epigenetics
Basic Epigenetic Mechanisms: Post Translational Modifications to Histones and Base Changes in DNA
Epigenetic modifications of histones and DNA include: Histone acetylation and methylation, and DNA methylation
Histone Methylation
Histone Acetylation Ac
Me
Me Me
DNA Methylation
Histone Proteins in Chromatin Can be Modified by Acetylation
Histone Acetylation
Histone Methylation Ac
Me Me Me
DNA Methylation
Epigenetic Changes can Alter Chromatin Structure and Regulate Gene Expression TF
TF
Ac
Ac
Ac
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Ac
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Gene expression
Gene expression
Gene expression (transcription) requires DNA to be physically accessible to transcription factors (TF) Epigenetic changes alter the structure of the chromatin, which determines whether DNA is accessible Open chromatin allows gene expression Closed chromatin prevents gene expression
In Cancer, Changes in Chromatin Structure Can Silence Tumor Suppressor Genes Normal cells
Ac
Ac
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Ac Ac
Cancer cells
Ac Ac
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Tumor suppressor gene expression
Tumor suppressor gene expression
Silencing of tumor suppressor genes, a major process in tumorigenesis, may result from epigenetic changes that condense chromatin structure
Balance of Histone Acetylation is a Key Factor in Transcriptional Regulation in Normal Cells HAT HISTONE ACETYLATION
TF
TF
Ac
Ac
Ac
Ac
Ac Ac
Ac Ac
Ac
Deacetylated Histones
Acetylated Histones
Closed chromatin Transcription factors cannot access DNA
Open chromatin Transcription factors can access DNA
Gene expression
Gene expression
Balance of Histone Acetylation is a Key Factor in Transcriptional Regulation in Normal Cells HAT HISTONE ACETYLATION
TF
TF
Ac
Ac
Ac
Ac
Ac Ac
Ac Ac
Ac
HISTONE DEACETYLATION
Deacetylated Histones Closed chromatin Transcription factors cannot access DNA Gene expression
HDAC HDAC
Acetylated Histones Open chromatin Transcription factors can access DNA Gene expression
Section 1: Importance of Epigenetics in Cancer
Section 2: Mechanisms of Epigenetics: Focus on Deacetylation
Section 3: Therapeutic Targeting of Epigenetics
Increased HDAC Activity Can Alter Gene Expression and Result in Cancer
TF
HDAC
Increased HDAC activity associated with certain tumors, can alter expression of genes involved in normal cell development, resulting in:
Loss of cell-cycle arrest
Inhibition of differentiation
Cell growth and proliferation
Evasion of apoptosis
Migration and metastasis
Gene expression
Cell nucleus
HDAC Inhibition Can Reverse Altered Gene Expression
Inhibition of HDAC activity can restore the balance of histone acetylation
Targeting HDAC activity may therefore allow re-expression of silenced genes to reverse oncogenesis
DAC Inhibitor HDAC
TF
Ac
Ac
Ac
Cell-cycle arrest Differentiation
Gene expression
Growth control Apoptosis Adhesion
Cell nucleus
Therapeutic Targeting of Both Histone and DNA Modifications Can Synergize DNMT Inhibitor DAC Inhibitor
DNMT
HDAC
TF Ac
Ac
Ac
Ac
Ac
Ac
Cell-cycle arrest Differentiation
Gene expression
Growth control Apoptosis Adhesion
Cell nucleus
Since DNA methylation and histone deacetylation can co-operate to silence tumor suppressors, inhibition of both DNMT and HDAC activities can synergize to restore expression of silenced genes
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