ATP-Dependent Chromatin Remodeling During Cortical Neurogenesis

Abstract

The generation of individual neurons (neurogenesis) during cortical development occurs in discrete steps that are subtly regulated and orchestrated to ensure normal histogenesis and function of the cortex. Notably, various gene expression programs are known to critically drive many facets of neurogenesis with a high level of specificity during brain development. Typically, precise regulation of gene expression patterns ensures that key events like proliferation and differentiation of neural progenitors, specification of neuronal subtypes, as well as migration and maturation of neurons in the developing cortex occur properly. ATP-dependent chromatin remodeling complexes regulate gene expression through utilization of energy from ATP hydrolysis to reorganize chromatin structure. These chromatin remodeling complexes are characteristically multimeric, with some capable of adopting functionally distinct conformations via subunit reconstitution to perform specific roles in major aspects of cortical neurogenesis. In this review, we highlight the functions of such chromatin remodelers during cortical development. We also bring together various proposed mechanisms by which ATP-dependent chromatin remodelers function individually or in concert, to specifically modulate vital steps in cortical neurogenesis.

Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms

“…Fine mapping of this locus in SCZ implicates INO80E and TMEM219 from prenatal brain, INO80E being the only gene in this locus implicated by both prenatal and adult data. INO80E is an interesting candidate, due to its similar role as the chromatin-helicase-DNA binding protein family, including CHD8, in chromatin remodeling during cortical neurogenesis (Clapier et al, 2017;Sokpor et al, 2018). Prenatal brain TWAS also implicated KCTD13, CTD-2574D22.2, PPP4C, and YPEL3, whereas MAPK3, DOC2A, and TAOK2, although implicated by adult brain expression data, are not supported by fine-mapping.…”

“…We highlight three of these genes: INO80 complex subunit E (INO80E), splicing factor 3b subunit 1 (SF3B1), and matrix AAA peptidase interacting protein 1 (MAIP1; C2orf47). INO80E is a component of a chromatin remodeling complex involved nucleosome spacing and modulates transcriptional regulation during corticogenesis (Ayala et al, 2018;Sokpor et al, 2018). SF3B1 is within a SCZ GWAS locus and is supported by an animal model of psychosis (Ingason et al, 2015).…”

Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks

“…The nervous system is a good target organ to examine DDR, since the distinct developmental stage allows us to look into difference of DDR and damage repair in proliferation, differentiation, and maturation of cells, as defective DDR and damage repair in the nervous system has severe consequences in humans 1 , 22 . Furthermore, dynamic changes of chromatin environment and epigenetic regulation are one of critical regulatory factors for the proper neurogenesis 23 , 24 . In the mouse model, exon 4 of Rsf1 encoding a part of the WHIM domains was floxed (Figure S1b , right), and then successfully deleted in a Nes-Cre line ( Rsf1 Nes-Cre as indicated in figures) (Figure S1c ), with no RSF1 protein detected throughout the central nervous system (Figure S1d ).…”

Druggable Transcriptional Networks in the Human Neurogenic Epigenome

“…The temporal stages of stemness, proliferation, neurogenesis, cell division, and differentiation are not precisely linear, but rather proceed in bursts of cell fate commitment and terminal differentiation. Different cell type-specific transcriptional networks of neurogenesis overlap with those of differentiation, because pluripotent neuronal stem-like blast cells acquire neuronal cell fate and switch from cell proliferation to neurogenic cell division in cerebral cortex (Sokpor et al, 2018).…”

“…4). These mutations in human neurologic disease and psychiatric disorders, as well as several human cancers, represent druggable candidates found within drug-disease networks (Ronan et al, 2013;Kadoch and Crabtree, 2015;Kadoch et al, 2017;Sokpor et al, 2018) . Figure 4 shows examples of npBAF and nBAF genes that are mutated in schizophrenia, autism spectrum disorder, Coffin-Siris and related neurodevelopmental disorders, cognitive impairment, and dementia in Lewy body disease.…”