Epigenetic regulation shapes gene expression without altering DNA sequences. This fascinating process involves DNA methylation, histone modifications, and chromatin structure changes. These mechanisms work together to control which genes are active or silent in different cells and situations.
Understanding epigenetics is crucial for grasping how genes are regulated beyond their DNA code. It explains phenomena like X-chromosome inactivation, genomic imprinting, and how environmental factors can influence gene expression across generations.
DNA Modifications
DNA Methylation and Imprinting
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- DNA methylation involves addition of methyl groups to cytosine bases in DNA
- Occurs primarily at CpG sites where cytosine is followed by guanine
- Methylation typically represses gene expression by preventing transcription factor binding
- Imprinting results from parent-specific DNA methylation patterns
- Imprinted genes express only one parental allele while silencing the other (Igf2 gene)
- Methylation patterns established during gametogenesis persist through embryonic development
- Errors in imprinting lead to developmental disorders (Prader-Willi syndrome)
X-Chromosome Inactivation and Epigenetic Inheritance
- X-chromosome inactivation compensates for gene dosage differences between males and females
- One X chromosome in female cells becomes highly condensed and transcriptionally inactive
- Process initiated by Xist RNA coating the future inactive X chromosome
- Inactivation maintained through DNA methylation and histone modifications
- Epigenetic inheritance involves transmission of gene expression patterns without DNA sequence changes
- Epigenetic marks can persist through cell divisions and sometimes across generations
- Environmental factors can influence epigenetic patterns (diet, stress, toxin exposure)
- Transgenerational epigenetic effects observed in plants and some animals (Agouti mouse model)
Histone Modifications
Types of Histone Modifications
- Histones undergo post-translational modifications on their amino acid tails
- Acetylation adds acetyl groups to lysine residues on histone tails
- Methylation adds methyl groups to lysine or arginine residues
- Phosphorylation adds phosphate groups to serine, threonine, or tyrosine residues
- Other modifications include ubiquitination, sumoylation, and ADP-ribosylation
- Modifications alter histone-DNA interactions and recruit regulatory proteins
- Histone code hypothesis suggests combinations of modifications determine gene activity
Effects of Specific Histone Modifications
- Acetylation generally promotes gene activation by loosening chromatin structure
- Histone acetyltransferases (HATs) add acetyl groups, histone deacetylases (HDACs) remove them
- Methylation effects depend on the specific residue and number of methyl groups added
- H3K4 methylation associated with active genes, H3K9 methylation with gene repression
- Phosphorylation often linked to chromatin condensation during cell division
- H3S10 phosphorylation correlates with chromosome condensation in mitosis
- Modifications work in concert to fine-tune gene expression (bivalent domains in stem cells)
Chromatin Structure
Chromatin Remodeling and Higher-Order Organization
- Chromatin remodeling alters DNA-histone interactions to regulate gene accessibility
- ATP-dependent chromatin remodeling complexes (SWI/SNF, ISWI, CHD, INO80) slide or evict nucleosomes
- Remodelers use energy from ATP hydrolysis to disrupt histone-DNA contacts
- Nucleosome positioning affects transcription factor binding and gene expression
- Higher-order chromatin structure includes 30nm fiber and topologically associating domains (TADs)
- TADs represent regions of increased interaction frequency in 3D genome organization
- Insulators and boundary elements separate active and repressed chromatin domains
- CTCF protein plays crucial role in establishing chromatin loops and TAD boundaries
Chromatin States and Gene Regulation
- Euchromatin represents loosely packed, transcriptionally active chromatin regions
- Heterochromatin consists of tightly packed, transcriptionally repressed regions
- Constitutive heterochromatin found at centromeres and telomeres, maintains genome stability
- Facultative heterochromatin can switch between active and repressed states (X-inactivation)
- Polycomb group proteins establish and maintain repressive chromatin states
- Trithorax group proteins promote active chromatin states and counteract Polycomb repression
- Bivalent chromatin domains in stem cells contain both active and repressive marks
- Enhancer elements regulate gene expression through long-range chromatin interactions
- Super-enhancers control expression of cell identity genes and oncogenes in cancer