Epigenetics LECTURE

Psychosis Spectrum

PSY 3360: Neurobiology of Psychosis

Epigenetics Overview

  • Definition: Epigenetics refers to modifications in gene function that influence gene expression without altering the underlying DNA sequence.

    • Changes are heritable and reversible.

    • Epigenetic regulation is characterized as:

    • Cell-specific: Different cells can have varying patterns of gene expression.

    • Developmentally dynamic: Changes can occur at different life stages.

    • Environmentally sensitive: External factors can influence epigenetic changes.

  • Epigenetic alterations have been increasingly implicated in neurological and psychiatric disorders.

    • Patterns can vary between individuals, tissues, and even single cells.

Major Epigenetic Mechanisms

  1. DNA Methylation

    • Involves the addition of a methyl group to cytosine at CpG sites.

    • Typically associated with reduced gene expression.

    • Stable but potentially reversible.

  2. Histone Modification

    • Histones form complexes with DNA in chromosomes called chromatin.

      • Chromatin can be tightly or loosely coiled.

      • Loosely coiled chromatin contains transcriptionally accessible DNA regions, while tightly coiled chromatin contains inactive DNA regions.

    • Types of histone modifications include:

      • Methylation (me)

      • Acetylation (ac)

      • Phosphorylation (pho)

      • Ubiquitination (ub)

      • SUMOylation (sum)

  3. Non-coding RNA Regulation

    • Majority (76–97%) of the human genome encodes non-coding RNAs (ncRNAs), which regulate gene expression without producing proteins.

    • Types of ncRNAs:

      • MicroRNAs (miRNAs): Small RNA molecules that play important roles in cellular processes including muscle differentiation, cardiac development, and neurogenesis.

      • Long non-coding RNAs (lncRNAs): Involved in various regulatory processes related to gene expression.

    • In schizophrenia, research focuses on microRNAs related to the 22q11.2 deletion syndrome involving the gene (DGCR8) that encodes a microRNA processing protein.

Environmental Influences on Epigenetic Modification

  • Factors affecting DNA methylation include:

    • Fertilization

    • Pregnancy

    • Infancy

    • Young adulthood

    • Senior age

    • Parent-of-origin (imprinted genes)

    • Maternal diet

    • Early life exposure to microbes

    • Environmental influences such as diet and lifestyle changes

Maternal Care and Epigenetic Programming

  • High licking/grooming (High-LG) vs Low licking/grooming (Low-LG) maternal care in rats leads to different stress outcomes in offspring:

    • High-LG mothers → offspring exhibit lower stress reactivity.

    • Low-LG mothers → offspring exhibit higher stress reactivity.

  • Mechanism: Epigenetic modification of the glucocorticoid receptor (GR) gene is responsible for these differences.

Epigenetic Modifications from Environmental Factors

  • A variety of environmental factors contribute to epigenetic changes, such as:

    • Prenatal or postnatal stress

    • Inhibitors of fetal neurogenesis

    • Maternal immune activation (infectious and non-infectious) during pregnancy

    • Nutritional deficiencies during gestation and postpartum

    • Exposure to drugs or toxicants

    • Reduced maternal care postpartum

  • Such factors lead to significant behavioral and neurobiological alterations associated with psychotic disorders, resulting in enduring changes in epigenetic profiles.

Personalized Medicine in Schizophrenia

  • Pharmacogenetics focuses on exploring genetic variants related to drug efficacy and response.

  • Summary of significant findings:

    • Studies have examined various polymorphisms and clinical responses to the antipsychotic medication risperidone (RIS).

    • Notable genetic variants associated with clinical outcomes:

    • DRD2, HTR2A, CYP2D6

    • Response to medication based on variants in genes such as GRM7, and GLP1R.

  • Example studies:

    • Kaur et al. (2017): Investigated DRD2 and HTR2A polymorphisms in Northern Indian patients and their response to risperidone.

    • Yu et al. (2018): Examined variants SLC1A1 in Han Chinese and associated them with drug response at a genome-wide significance level.

Pharmacoepigenetics Overview

  • Definition: Pharmacoepigenetics examines how epigenetic variations influence drug response.

    • Epigenome can be:

    • Dysregulated in illnesses

    • Modified by medications

  • Implications:

    • Potential explanations for variability in treatment response, side effects, and treatment resistance.

  • Summary of studies exploring DNA methylation's relationship with antipsychotic medications:

    • Research indicated significant methylation patterns associated with drug efficacy, sometimes identifying differentially methylated regions in schizophrenia patients compared to controls.

    • Studies utilized methodologies such as Infinium 450K array, bisulfite sequencing, and MassARRAY analyzers to investigate changes in methylation and pharmacotherapy responses.