Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development

Abstract

The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.

The BAF (BRG1/BRM-Associated Factor) chromatin-remodeling complex exhibits ethanol sensitivity in fetal neural progenitor cells and regulates transcription at the miR-9-2 encoding gene locus

“…BAF155 and BAF170 are core components of the neuronal lineage-specific Baf (nBAF) complex (Ho and Crabtree, 2010), and simultaneous knockdown of both BAF155 and BAF170 have been shown to be effective in inactivating the BAF complex (Nguyen et al, 2016). We therefore used siRNAs to simultaneously knockdown both BAF155 and 170, to disrupt the BAF complex.…”

“…In the current study, ChIP analysis indicated that BRG1 could bind to both DNAse I hypersensitive and resistant sites, suggesting that the BAF complex associates with both euchromatic (transcriptionally assessable) and heterochromatic methylated CpG islands within the pri-miR-9-2 locus. Moreover, combinational knockdown of BAF155 and BAF170, which is required for BAF-complex dissolution (Nguyen et al, 2016), resulted in approximately 50% reduction in miR-9. This outcome supports a model for the BAF-complex as means for increasing chromatin accessibility to promote miR-9 gene transcription.…”

“…The BAF complex (Nguyen et al, 2016) and miR-9 (Pappalardo-Carter et al, 2013) are both important for promoting brain growth. Our data further indicate that the BAF-complex is an epigenetic regulator of the pri-miR-9-2 locus at least, in an ex vivo model for fetal NSCs.…”

Epigenetic cues modulating the generation of cell‐type diversity in the cerebral cortex

“…Conditional BAF155/170 deletion is accompanied by a global shift from activating H3K9ac to repressive H3K27me2/me3 marks (Nguyen et al . ). What are the exclusive functions of BAF170 and BAF155, respectively, during RGP‐mediated neurogenesis?…”

“…Conditional BAF155/170 double mutants display reduced numbers of proliferative RGPs, dramatic thinning of the cortical SVZ and extensive loss of projection neurons, emphasizing a crucial function of BAF complexes in corticogenesis (Narayanan et al 2015). Conditional BAF155/170 deletion is accompanied by a global shift from activating H3K9ac to repressive H3K27me2/me3 marks (Nguyen et al 2016). What are the exclusive functions of BAF170 and BAF155, respectively, during RGP-mediated neurogenesis?…”