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Review
. 2022 Oct 13:10:1001701.
doi: 10.3389/fcell.2022.1001701. eCollection 2022.

Epigenetics of neural differentiation: Spotlight on enhancers

Mayela Giacoman-Lozano  1 , César Meléndez-Ramírez  2   3 , Emmanuel Martinez-Ledesma  1   4 , Raquel Cuevas-Diaz Duran  1 , Iván Velasco  2   3
Affiliations
Review

Epigenetics of neural differentiation: Spotlight on enhancers

Mayela Giacoman-Lozano et al. Front Cell Dev Biol. .

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.

Keywords: cell-type specific; enhancers; epigenetics; neural induction; neurogenesis; transcription regulation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Chromatin landscape from an enhancer perspective. (A) Cell nucleus and densely packed chromatin (heterochromatin) in intergenic regions. (B) CTCF and YY1, architectural proteins of the chromatin at the anchor of a chromatin loop. (C) Promotor region immediately upstream a TSS, marked by H3K27ac and H3K4me3 posttranslational histone modifications, open chromatin, general TF binging, RNA POL II recruitment. (D) Mediator complex brings together an enhancer and a promoter. (E) An enhancer region marked by H3K27ac and H3K4me1 posttranslational histone modifications, open chromatin, TF binging, RNA POL II recruitment, and eRNA transcription. (F) DNA methylation in CpGs.
FIGURE 2
FIGURE 2
Enhancer identification and characterization in human neurons. (A) Human neurons for scientific study can come from different sources, like postmortem human brains at any stage (fetal or adult), they could be in vitro generated by ESCs and iPSCs differentiation or derived from immortalized cell lines, like LUMES and SH-SY5Y lines. (B) Contact matrix showing topology as measured by HiC on a genomic locus; information regarding tridimensional contacts in the genome can be also assessed by 3C, 4C, 5C, and HiC derived techniques. (C) A hypothetical neural genomic locus containing two enhancers and a gene promoter. (D) Transcription can be measured by RNA-seq and CAGE-seq, where promoters and enhancers are transcriptionally active. (E) Chromatin accessibility is another major feature of active regulatory elements, it can be assessed by ATAC-seq. (F) Enhancers and promoters can be mapped across the genome by assessing chromatin histone modifications and TF binding by ChIP-seq and CUT&Tag. (G) Regulatory regions are enriched in TFs binding motifs, it is possible to perform computational analysis on these elements to predict their function. (H) Some disease-associated SNPs lie in non-coding neural regulatory regions of the genome.
FIGURE 3
FIGURE 3
A schematic representation of enhancer activity and enhancer-promoter interactions associated to a neural locus in a NPC and a fully differentiated neuron. (A) In NPCs, enhancers targeting neurogenesis and neuron-related genes are interacting with promoters, however since enhancers are inactive (primed or poised) genes are not transcribed. Thus, SNPs within these enhancer regions have no effect on gene transcription. (B) After neuronal cell fate specification, neurogenesis and neuron-related genes are transcribed when enhancers become active. However, SNPs within active enhancers may have an effect disrupting the binding of TFs and coactivators.
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