Week 4

Epigenetics Overview

Chapters Covered: 17.4, 18, 22.7

Key Concepts:

• Histone Modifications: Post-translational modifications of histone proteins, such as methylation and acetylation, influence chromatin structure and gene expression.

• RNA: Non-coding RNAs play critical roles in regulating gene expression and maintaining cellular functions.

• Heritable Silencing: Epigenetic mechanisms can lead to heritable changes in gene expression without altering the DNA sequence.

• DNA Methylation: The addition of methyl groups to DNA molecules, primarily at cytosine bases, which can silence genes.

Correction

• Somatic Cells: Refers to all body cells excluding sperm and egg (germ) cells. These cells undergo various epigenetic changes that can influence their function and behavior, impacting organismal health and development.

Definition of Epigenetics

• Best Definition: The study of mechanisms that lead to a reversible change in gene expression that can be passed from cell to cell (heritable), without changing the DNA sequence itself. Understanding these mechanisms is crucial for insights into development, differentiation, and disease.

• Examples: Major epigenetic mechanisms include DNA methylation, chromatin remodeling, and histone modification, each contributing to the regulation of gene expression and cellular functions.

Epigenetic Inheritance

• Occurs when an epimutation—an epigenetic alteration—happens in a germ cell, which can subsequently be passed to the next generation and affect phenotypic traits.

Targeting Genes for Epigenetic Changes

• Current Research Focus: Investigating the specific mechanisms that determine which genes or chromosomes are targeted for epigenetic modifications, with implications for understanding various diseases and developmental processes.

• Role of Transcription Factors: Transcription factors may bind to specific genes, facilitating or inhibiting the recruitment of epigenetic modifiers, thus initiating epigenetic changes.

• Role of Non-coding RNAs (ncRNAs): These molecules are increasingly recognized for their role in establishing epigenetic events by binding to specific sites on DNA or chromatin, thereby influencing modulator proteins that alter DNA structure.

Non-coding RNAs (ncRNAs)

• Types of ncRNAs: Include endogenous microRNAs (miRNAs), small interfering RNAs (endo-siRNAs), PIWI-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), tRNA-derived small RNAs (tsRNAs), natural antisense transcripts (NATs), circular RNAs (circRNAs). Each type has distinct functions that contribute to gene regulation.

• Functions of ncRNAs:

  • Affect transcription and translation processes, thereby influencing protein synthesis.

  • Bind to multiple proteins simultaneously, acting as key regulators in various cellular processes.

  • Serve as scaffolds, allowing for the formation of protein complexes that can modulate gene expression.

  • Guide other molecules to specific locations within a cell, contributing to precise cellular responses.

  • Alter protein structures and function, even acting as ribozymes to catalyze chemical reactions.

  • Block cellular processes or function as decoys that influence the action of other ncRNAs, thereby modulating gene expression levels effectively.

Chromatin Structure and Transcription

• Example: HOTAIR, a specific non-coding RNA that acts as a scaffold for recruiting histone-modifying enzymes to target genes, influencing methylation and demethylation pathways, ultimately inhibiting transcription of certain genes, thus impacting developmental outcomes and potential disease states.

Epigenetic Regulation

• Developmental Changes: Cell differentiation and genomic imprinting are critical processes that are regulated by epigenetic mechanisms, allowing cells to adopt specialized functions.

• Environmental Agents: Various environmental factors such as toxins, dietary components, temperature fluctuations, and lifestyle choices can act as regulators of epigenetic changes, influencing health outcomes across generations.

• The Exposome: The totality of environmental exposures throughout an individual's lifespan can significantly affect the epigenome, transcriptome, proteome, and metabolome, thereby influencing phenotypic expressions and health conditions.

Environmental Impact on Epigenetics

• Neutrophil Chemotaxis: Pollution demonstrates how decreased DNA methyltransferase activity due to environmental toxins can trigger inflammatory responses via MAPK (mitogen-activated protein kinase) pathways, impacting immune functions.

• Alcohol and Cancer Mechanisms:

  • Mechanism A: Acetaldehyde generated from alcohol consumption can induce direct DNA damage.

  • Mechanism B: Alcohol triggers oxidative stress, which leads to increased DNA damage.

  • Mechanism C: Changes in hormone levels due to alcohol consumption can elevate cancer risks.

  • Mechanism D: Alcohol consumption can enhance the absorption of carcinogens, further increasing cancer development risk.

Epigenetic Diseases

• Examples:

  • ATR-X Syndrome: A genetic disorder characterized by intellectual disabilities and a-thalassemia resulting from epigenetic mutations.

  • Fragile X Syndrome: Associated with chromosome instability due to epigenetic alterations.

  • Cancer: Resulting from disruptions in normal epigenetic pathways and cellular processes, leading to uncontrolled cell proliferation.

Tumor-suppressor vs Oncogene

• Normal Function: Tumor-suppressor genes function to negatively regulate the cell cycle, whereas proto-oncogenes serve to positively regulate cellular growth and division.

• Effects of Mutations: Mutations in tumor-suppressor genes result in loss of function, leading to unchecked cell division; in contrast, mutations in proto-oncogenes lead to gain of function, contributing to cancer development.

Epigenetic Drugs

• Targets: Pharmacological agents such as 5-Azacytidine and Valproic Acid specifically target DNA methylation patterns, while others may impact histone acetylation and deacetylation pathways to address various epigenetic disorders.

Parenting Behaviors

• Observations indicate that high levels of licking/grooming behaviors in animal models lead to lower anxiety levels in offspring by enhancing glucocorticoid receptor expression. Conversely, low licking/grooming behaviors have been linked to an increased propensity for anxiety in offspring, highlighting the impact of parental care on epigenetic regulation of stress responses.

Agouti Gene and Nutrition

• Gene Functionality: The methylation state of the Agouti gene significantly affects its expression, which in turn influences traits such as coat color and health conditions in offspring.

• Dietary Influence: Research indicates that supplementation of diets can lead to healthier and predominantly brown offspring, demonstrating how nutrition can have substantial epigenetic effects on phenotype and health outcomes.

Importance of Methylation

• Methylation Patterns: Disruption of normal methylation patterns by environmental factors, such as BPA (bisphenol A), poses risks that may be inherited by future generations, affecting health outcomes and disease susceptibility.

Royal Jelly and Epigenetics

• Effect on Dnmt3: Royal jelly has been shown to influence the expression of genes crucial for queen bee development through modulation of DNMT3 (DNA methyltransferase 3), exemplifying how dietary factors can impact epigenetic programming.

Summary

• The interplay of environmental, dietary, and behavioral factors has profound implications for epigenetic mechanisms, influencing health outcomes and disease susceptibilities across generations. The dynamic nature of epigenetic modifications underscores the potential for therapeutic interventions aimed at correcting epigenetic abnormalities and enhancing health.