8.3 Epigenetic regulation (DNA methylation, histone modifications)

Epigenetic regulation shapes gene expression without changing DNA sequences. It's like a conductor directing an orchestra, telling genes when to play and when to stay silent during development. This process involves DNA methylation and histone modifications.

These mechanisms are crucial for cell fate decisions and tissue-specific gene expression. They guide stem cells to become specialized, maintain cell identity, and allow cells to respond to their environment. It's like cells writing their own instruction manuals as they grow and change.

Epigenetics and Gene Regulation

Epigenetic Mechanisms and Their Role

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• Epigenetics involves heritable changes in gene expression without DNA sequence alterations
• Regulates gene expression during development by controlling gene activation in specific cell types and developmental stages
• Encompasses dynamic and reversible modifications allowing flexible gene regulation throughout life
• Includes DNA methylation, histone modifications, and non-coding RNAs modulating chromatin structure and accessibility
• Essential for X-chromosome inactivation, genomic imprinting, and cellular differentiation during embryonic development
• Disruptions lead to developmental abnormalities and diseases (cancer, neurological disorders)

Epigenetic Processes in Development

• Crucial for establishing cell fate and tissue-specific gene expression patterns
• Guides stem cell differentiation by activating lineage-specific genes and repressing pluripotency genes
• Facilitates cellular memory, maintaining cell identity through multiple cell divisions
• Enables developmental plasticity, allowing cells to respond to environmental cues
• Regulates timing of gene expression during embryogenesis (HOX genes)
• Contributes to organ development and tissue homeostasis (liver, brain, immune system)

DNA Methylation: Gene Silencing

Mechanism and Enzymes

• Involves adding methyl group to cytosine base in CpG dinucleotides, catalyzed by DNA methyltransferases (DNMTs)
• Occurs primarily at 5' carbon of cytosine residues, forming 5-methylcytosine (5mC)
• Established and maintained by different DNMT classes
  • DNMT1 performs maintenance methylation
  • DNMT3A/B catalyze de novo methylation
• Methylated CpG islands in promoter regions typically lead to transcriptional repression
• Prevents transcription factor binding or recruits repressive protein complexes

Silencing Mechanisms and Developmental Dynamics

• DNA methylation silences genes through two primary mechanisms
  • Direct interference with transcription factor binding to recognition sequences
  • Recruitment of methyl-CpG-binding proteins (MBPs) interacting with histone-modifying enzymes
• Creates repressive chromatin environment
• Patterns change dynamically during development
  • Global demethylation occurs during gametogenesis
  • Remethylation events take place in early embryogenesis
• Regulates genomic imprinting (IGF2/H19 locus)
• Controls tissue-specific gene expression (globin genes in erythrocytes)

Histone Modifications: Chromatin Structure

Types and Effects of Modifications

• Involve covalent alterations to N-terminal tails of histone proteins
• Include acetylation, methylation, phosphorylation, and ubiquitination
• Histone acetylation promotes open chromatin structure and increased gene expression
  • Catalyzed by histone acetyltransferases (HATs)
• Histone deacetylation leads to compact chromatin structure and gene repression
  • Mediated by histone deacetylases (HDACs)
• Histone methylation effects vary based on residue modified and degree of methylation
  • H3K4me3 associates with active promoters
  • H3K27me3 correlates with gene repression
  • H3K9me3 links to heterochromatin formation
• Histone phosphorylation associates with chromatin condensation during cell division and DNA damage response

Histone Code and Chromatin Remodeling

• Combination of modifications creates "histone code" read by effector proteins
• Influences chromatin structure and gene expression
• Recruits chromatin remodeling complexes (SWI/SNF, ISWI)
• Regulates enhancer-promoter interactions (H3K27ac marks active enhancers)
• Facilitates DNA repair processes (H2AX phosphorylation in double-strand breaks)
• Guides epigenetic reprogramming during cellular differentiation and development

Epigenetic Inheritance: Development and Disease

Transgenerational Epigenetic Inheritance

• Transmits epigenetic marks across generations without DNA sequence changes
• Occurs through incomplete erasure of marks during gametogenesis and early embryonic development
• Contributes to developmental plasticity, allowing organisms to adapt phenotypes across generations
• Examples in development include
  • Genomic imprinting with parent-of-origin-specific gene expression
  • Paramutation where one allele induces heritable change in the other allele
• Environmental factors influence epigenetic patterns
  • Nutrition (maternal diet affecting offspring metabolism)
  • Stress (paternal stress impacting offspring stress response)
  • Toxin exposure (endocrine disruptors altering reproductive development)

Epigenetics in Disease and Therapeutic Potential

• Aberrant epigenetic inheritance implicated in various diseases
  • Cancer (inherited epigenetic silencing of tumor suppressor genes)
  • Neurodevelopmental disorders (autism, schizophrenia)
  • Metabolic disorders (altered epigenetic patterns affecting energy metabolism and obesity risk)
• Understanding mechanisms crucial for developing therapeutic interventions
  • DNA demethylating agents (5-azacytidine for myelodysplastic syndromes)
  • Histone deacetylase inhibitors (vorinostat for cutaneous T-cell lymphoma)
• Potential for epigenetic biomarkers in disease diagnosis and prognosis
• Epigenetic editing technologies (CRISPR-dCas9) offer targeted modification of epigenetic marks
• Nutritional interventions targeting epigenetic mechanisms (folate supplementation)