Epigenetics of neural differentiation: Spotlight on enhancers

Abstract

Neural induction, both in vivo and in vitro, includes cellular and molecular changes that result in phenotypic specialization related to specific transcriptional patterns. These changes are achieved through the implementation of complex gene regulatory networks. Furthermore, these regulatory networks are influenced by epigenetic mechanisms that drive cell heterogeneity and cell-type specificity, in a controlled and complex manner. Epigenetic marks, such as DNA methylation and histone residue modifications, are highly dynamic and stage-specific during neurogenesis. Genome-wide assessment of these modifications has allowed the identification of distinct non-coding regulatory regions involved in neural cell differentiation, maturation, and plasticity. Enhancers are short DNA regulatory regions that bind transcription factors (TFs) and interact with gene promoters to increase transcriptional activity. They are of special interest in neuroscience because they are enriched in neurons and underlie the cell-type-specificity and dynamic gene expression profiles. Classification of the full epigenomic landscape of neural subtypes is important to better understand gene regulation in brain health and during diseases. Advances in novel next-generation high-throughput sequencing technologies, genome editing, Genome-wide association studies (GWAS), stem cell differentiation, and brain organoids are allowing researchers to study brain development and neurodegenerative diseases with an unprecedented resolution. Herein, we describe important epigenetic mechanisms related to neurogenesis in mammals. We focus on the potential roles of neural enhancers in neurogenesis, cell-fate commitment, and neuronal plasticity. We review recent findings on epigenetic regulatory mechanisms involved in neurogenesis and discuss how sequence variations within enhancers may be associated with genetic risk for neurological and psychiatric disorders.

Acquisition of neural fate by combination of BMP blockade and chromatin modification

“…Polycomb group (PcG) proteins have been shown to influence these chromosomal dynamics 14 , 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 and to regulate gene expression through chromatin modifications. 34 PcG proteins form two major chromatin-modifying complexes, known as Polycomb repressive complexes 1 and 2 (PRC1 and PRC2).…”

Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits

“…Enhancers are cis-regulatory elements important for controlling gene expression, and DNA methylation at both CA and CG sites control enhancer activity through effects on transcription factor binding and recruitment of methyl-DNA binding factors (Clemens & Gabel, 2020; Giacoman-Lozano et al, 2022; Kozlenkov et al, 2014). To determine if DNMT3A mutants have varied disruption of enhancers corresponding to their differential changes in DNA methylation, we examined enhancer activity by ChIP-seq of Histone H3 lysine 27 acetylation (H3K27ac), a histone modification correlated with active enhancers.…”

Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits

“…Enhancers are cis -regulatory elements that regulate gene expression, and DNA methylation at both CA and CG sites modulates enhancer activity through effects on transcription factor binding and recruitment of methyl-DNA binding factors. 37 – 39 We examined enhancer activity using chromatin immunoprecipitation sequencing (ChIP-seq) analysis of histone H3 lysine 27 acetylation (H3K27ac; a histone modification correlated with active enhancers 40 ) in the cortex of 8-week-old P900L and R878H mutants to determine if enhancer disruption mirrors differential DNA methylation changes. Profiles of acetylation in mutants and associated controls showed enrichment at promoters and putative enhancers consistent with published cortical profiles ( Figures 5A and 5B ; Figure S4C ).…”