Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders

Abstract

The ATP-dependent BRG1/BRM associated factor (BAF) chromatin remodeling complexes are crucial in regulating gene expression by controlling chromatin dynamics. Over the last decade, it has become increasingly clear that during neural development in mammals, distinct ontogenetic stage-specific BAF complexes derived from combinatorial assembly of their subunits are formed in neural progenitors and post-mitotic neural cells. Proper functioning of the BAF complexes plays critical roles in neural development, including the establishment and maintenance of neural fates and functionality. Indeed, recent human exome sequencing and genome-wide association studies have revealed that mutations in BAF complex subunits are linked to neurodevelopmental disorders such as Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, Kleefstra's syndrome spectrum, Hirschsprung's disease, autism spectrum disorder, and schizophrenia. In this review, we focus on the latest insights into the functions of BAF complexes during neural development and the plausible mechanistic basis of how mutations in known BAF subunits are associated with certain neurodevelopmental disorders.

Keywords: BAF (mSWI/SNF) complex; chromatin remodeling; epigenetic regulation; neural development; neurodevelopmental disorder.

Figure 1

Chromatin remodeling BAF (mSWI/SNF) complex in neural development and disorders. (A) The BAF complex, epigenetic factors (including non-coding [nc] RNA), and transcription factors (TF) control gene expression. TFs and ncRNAs bind to specific DNA sequences. The recruitment of BAF complexes and other epigenetic factors on the genome leads to altered epigenetic marks (e.g., histone acetylation, Ac; histone methylation, Me) and chromatin structure in order to activate or repress a specific gene expression program in cell lineages. Many BAF subunits as indicated, regulate distinct processes of neural development. (B) The presence of known BAF subunits in different BAF complexes in neural cells is indicated. The mutation of genes encoding for the noted BAF subunits has been reported in various neurological disorders.

Figure 2

Exon-structure of the genes encoding for BAF subunits and sites of the pathogenic mutations in neurodevelopmental disorders. The specific functional domains are also shown: ARID, A-T rich interaction domain; QLQ, Gln, Leu, Gln motif; HSA, small helicase/SANT-associated domain; SNF, sucrose/non-fermenting domain; BROMO, bromodomain; HMG, high-mobility group domain; RFX, RFX-like DNA binding domain; C2H2 ZF, C2H2 zinc fingers.

Figure 3

The mouse and iPSC-derived mini-brain organoid pipeline for modeling human brain disorders. Candidates of mutations involved in brain disorders are identified using exome sequencing with DNA samples from patients. When mouse orthologs of candidate genes are identified, they can be edited. Subsequently, phenotypic studies are used to assess validity of the model. Upon validation, reverse genetics approach with genome editing will be applied to restore phenotypes.