Epigenomically Bistable Regions across Neuron-Specific Genes Govern Neuron Eligibility to a Coding Ensemble in the Hippocampus

Cell Reports · 2020 · 18 citations

• Neuroscience
• Biology
• Genetics

Sensory inputs activate sparse neuronal ensembles in the dentate gyrus of the hippocampus, but how eligibility of individual neurons to recruitment is determined remains elusive. We identify thousands of largely bistable (CpG methylated or unmethylated) regions within neuronal gene bodies, established during mouse dentate gyrus development. Reducing DNA methylation and the proportion of the methylated epialleles at bistable regions compromises novel context-induced neuronal activation. Conversely, increasing methylation and the frequency of the methylated epialleles at bistable regions enhances intrinsic excitability. Single-nucleus profiling reveals enrichment of specific epialleles related to a subset of primarily exonic, bistable regions in activated neurons. Genes displaying both differential methylation and expression in activated neurons define a network of proteins regulating neuronal excitability and structural plasticity. We propose a model in which bistable regions create neuron heterogeneity and constellations of exonic methylation, which may contribute to cell-specific gene expression, excitability, and eligibility to a coding ensemble.

Epigenetic Neuropharmacology: Drugs Affecting the Epigenome in the Brain

The Annual Review of Pharmacology and Toxicology · 2020 · 30 citations

• Neuroscience
• Medicine
• Bioinformatics

This review explores how different classes of drugs, including those with therapeutic and abuse potential, alter brain functions and behavior via the epigenome. Epigenetics, in its simplest interpretation, is the study of the regulation of a genes' transcriptional potential. The epigenome is established during development but is malleable throughout life by a wide variety of drugs, with both clinical utility and abuse potential. An epigenetic effect can be central to the drug's therapeutic or abuse potential, or it can be independent from the main effect but nevertheless produce beneficial or adverse side effects. Here, I discuss the various epigenetic effects of main pharmacological drug classes, including antidepressants, antiepileptics, and drugs of abuse.