The npBAF to nBAF Chromatin Switch Regulates Cell Cycle Exit in the Developing Mammalian Cortex

Abstract

Nervous system development is orchestrated by tightly-regulated progenitor cell divisions, followed by differentiation at precise but varying times across different regions. As progenitors exit the cell cycle, they initiate a subunit switch of the mSWI/SNF or npBAF complex to generate neuron-specific nBAF complexes. These chromatin regulatory complexes play dosage-sensitive roles in neural development and are frequently mutated in neurodevelopmental disorders. Here we manipulated the timing of BAF subunit exchange in the developing mouse brain and find that deletion of the npBAF subunit BAF53a blocks progenitor proliferation, leading to impaired neurogenesis. We show that npBAF complexes regulate cell cycle progression by antagonizing Polycomb complexes to promote chromatin accessibility at cell cycle and NPC identity genes. Replacement of the actin-related protein, Actl6a (BAF53a) by the neuron-specific actin-related protein, Actl6b (BAF53b), but not other regulators of proliferation, rescues progenitors by promoting neuronal differentiation. We propose that the function of the npBAF to nBAF chromatin switch is to control progenitor cell cycle exit and promote synchronous neural differentiation.

Identification and validation of biomarkers based on cellular senescence in mild cognitive impairment

“…Frontiers in Aging Neuroscience 11 frontiersin.org and microglia activation, resulting in the occurrence and progression of neurodegenerative diseases, such as MCI, AD, among others (Akterin et al, 2006;Ghosh et al, 2015;Buccellato et al, 2021). In terms of the results of GO-MF and GO-CC, most of genes or pathways are principally associated with the regulation of cell cycle and the self-renewal or proliferative capacity of cells (Simone, 2006;Gupta et al, 2020;Braun et al, 2021;Mitra et al, 2022). In term of MF, mounting evidence showed that sequence-specific activators and repressors interact with coregulators, which in turn either stimulate or inhibit the binding or function (or both) of some transcription complex (Mannervik et al, 1999).…”

ASCL1 interacts with the mSWI/SNF at distal regulatory elements to regulate neural differentiation

“…Given the evidence that ASCL1 acts as a chromatin remodeling factor (with or without pioneer activity) in differentiating human neural cultures, we hypothesized that ASCL1 may regulate chromatin states by interacting with chromatin remodelers, and specifically with ATPasedependent chromatin remodeling complexes (Zaret and Carroll, 2011). mSWI/SNF or BRG1/BRM associated factor (BAF) complexes are evolutionary conserved ATP-dependent chromatin remodeling complexes with pivotal roles in neural development (Braun et al, 2021;Lessard et al, 2007;Yoo et al, 2009). Because our above data support ASCL1 peak expression coinciding with a progenitor state poised to differentiate, we hypothesized that ASCL1 functionally interacts with mSWI/SNF complexes at this crucial stage of neurogenesis.…”

“…Importantly, changes in the combinatorial assembly of BAF complexes underpin the transition from neural progenitors to neurons in vivo and in vitro (Lessard et al, 2007;Staahl et al, 2013;Yoo et al, 2009), with specific subunits incorporating in progenitor-specific (npBAF) or neuronal-specific (nBAF) complexes. The developmental overlap of npBAF and proneural transcription factors was recently highlighted by the demonstration that conditional deletion of npBAF subunit ACTL6A in mouse cortex leads to decreased chromatin accessibility at proneural TF binding sites, including ASCL1 (Braun et al, 2021). We therefore hypothesized that the pioneer TF ASCL1 may interact with mBAF SWI/SNF complexes to regulate chromatin accessibility at neurogenic loci to coordinate neurodifferentiation.…”