Invited Review: Epigenetics in neurodevelopment

Abstract

Neural development requires the orchestration of dynamic changes in gene expression to regulate cell fate decisions. This regulation is heavily influenced by epigenetics, heritable changes in gene expression not directly explained by genomic information alone. An understanding of the complexity of epigenetic regulation is rapidly emerging through the development of novel technologies that can assay various features of epigenetics and gene regulation. Here, we provide a broad overview of several commonly investigated modes of epigenetic regulation, including DNA methylation, histone modifications, noncoding RNAs, as well as epitranscriptomics that describe modifications of RNA, in neurodevelopment and diseases. Rather than functioning in isolation, it is being increasingly appreciated that these various modes of gene regulation are dynamically interactive and coordinate the complex nature of neurodevelopment along multiple axes. Future work investigating these interactions will likely utilize 'multi-omic' strategies that assay cell fate dynamics in a high-dimensional and high-throughput fashion. Novel human neurodevelopmental models including iPSC and cerebral organoid systems may provide further insight into human-specific features of neurodevelopment and diseases.

Keywords: DNA methylation; chromatin remodelling; developmental disorder; epitranscriptomics; neurogenesis.

Figure 1.. Regions of Mammalian Neurodevelopment.

(A) Embryonic neurodevelopment requires a complex orchestration of various cell types to generate the mammalian brain (red rectangle). As much of the brain becomes fully mature, enduring regions of adult neurogenesis have been characterized in the subventricular zone (red rectangle: top) and subgranular zone of the hippocampus (red rectangle: bottom). The degree to which this occurs in adult humans is an area of active investigation and debate. (B) Neural stem cells have several features including the process of self-renewal from stem cells that can become quiescent. Active neural stem cells can differentiate into multiple progeny including cells of neuronal, oligodendrocyte, and astrocyte lineages. Neuronal lineage cells (Neural progenitor cells) often undergo cellular expansion prior to neuron differentiation and subsequent maturation.

Figure 2.. Epigenetic Mechanisms of Gene Regulation

(A) Epigenetic regulation of higher ordered structures begins on the level of accessibility of chromatin. A-type chromatin (euchromatin) refers to open chromatin that is accessible for transcription, while B-type (heterochromatin) chromatin refers to closed chromatin that is typically association with gene inactivity. These areas of open chromatin can form chromatin loops that generate 3-dimensional structures that allow for long-range interactions that are not directly observable from the 2-dimensional sequence. (B) Long range interactions generated by 3-dimensional chromatin loops can form enhancer complexes, wherein transcription factors can bind to enhancer regions that are distal to the promoter region in 2-dimensions to influence gene expression. These enhancer regions are associated with histone modifications including H3K27ac (pictured), H3K4me1, as well as the enhancer-associated p300 protein. Promoter regions can be either inactive, which is associated with the Polycomb Repressive Complex-group catalysed H3K27me3 (pictured) or active, which is associated with the Trithorax group catalysed H3K4me3 (pictured). Regions with both H3K27me3 and H3K4me3 are considered inactive but poised for transcription. Removal of H3K27me3 by histone demethylases (KDM family proteins) can lead to transcriptional activation. (C) DNA methylation is written by DNA methyltransferases (DNMTs) and is traditionally associated with gene silencing due to interactions with MECP2. 5mC DNA methylation is removed through oxidation to 5hmC by TET family proteins and subsequent TDG-mediated excision, leading to base excision repair. MECP2 does not bind to 5hmCG, which is associated with regions of transcriptional activation. Transcription can be regulated by m⁶A modification on the RNA strand. This modification is written by METTL family proteins, read by various readers including YTHDC1, and enzymatically removed by various erases including FTO. m⁶A modification has diverse roles including regulating mRNA metabolism and translation and mediating RNA nuclear transport. Non-coding RNAs, including long-noncoding RNAs (lncRNAs), frequently occur on the anti-sense strand of mRNAs. These lncRNAs can operate locally in cis or distal to the area of transcription in trans in order to regulate gene expression.