Chromatin Regulation by BAF170 Controls Cerebral Cortical Size and Thickness

Abstract

Increased cortical size is essential to the enhanced intellectual capacity of primates during mammalian evolution. The mechanisms that control cortical size are largely unknown. Here, we show that mammalian BAF170, a subunit of the chromatin remodeling complex mSWI/SNF, is an intrinsic factor that controls cortical size. We find that conditional deletion of BAF170 promotes indirect neurogenesis by increasing the pool of intermediate progenitors (IPs) and results in an enlarged cortex, whereas cortex-specific BAF170 overexpression results in the opposite phenotype. Mechanistically, BAF170 competes with BAF155 subunit in the BAF complex, affecting euchromatin structure and thereby modulating the binding efficiency of the Pax6/REST-corepressor complex to Pax6 target genes that regulate the generation of IPs and late cortical progenitors. Our findings reveal a molecular mechanism mediated by the mSWI/SNF chromatin-remodeling complex that controls cortical architecture.

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

“…23,26,27 Conversely, little BAF170 is expressed in stem/progenitor cells (e.g., embryonic stem cells, or ESCs) and at higher levels in differentiated cells (e.g., neurons). 23,26,27 We hypothesized that although only low expression levels are detected for BAF170 in proliferating ESCs and for BAF155 in post-mitotic neurons, this expression is necessary and sufficient to stabilize the embryonic stem cell (es) BAF and neuronal (n)BAF complexes. Indeed, when we derived ESC lines from blastocysts and primary neurons from forebrains (both representing the dcKO_CAG-Cre genotype), we found that the depletion of BAF155 and BAF170 in these cultured cells led to the loss of BAF subunit expression at the protein level.…”

“…23,28 However, when we examined epigenetic marks in cortex-specific dcKO_Emx1-Cre mice, which lacked entire BAF complexes, we observed a global reduction in euchromatin along with increased H3K27me2/3 and decreased H3K9Ac in the developing cortex during both embryonic and perinatal stages, as assessed by assays such as ChIP-Seq, immunohistochemistry, and western blotting. 21 Thus, our data showed for the first time that the presence of BAF complexes is needed to maintain the balance between global repression and local activation of epigenetic programs during cortical development.…”

A schizophrenia-associated HLA locus affects thalamus volume and asymmetry

“…Both of these genes are expressed in the thalamus (Allen Brain Atlas: http://human.brain-map.org; Braineac: http://www.braineac.org/ (Ramasamy et al, 2014)), and Chip-seq data in mouse brain has suggested that their homologues (H2-K1 and Znrd1) are regulated by the transcriptional factor Pax6 (Xie et al, 2013), a major actor in the developing central nervous system. Notably Pax6 interacts with Baf150 and Baf177 to regulate cerebral size and thickness (Tuoc et al, 2013;Xie et al, 2013). Furthermore, both HLA-A and ZNRD1 contain SNPs associated with schizophrenia by GWAS; rs2524005 is intronic in HLA-A (Bergen et al, 2012) and rs8321 is in the 3 0 untranslated region of ZNRD1 (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013b).…”

<i>ARID1B</i>-mediated disorders: Mutations and possible mechanisms

“…BAF170 has been found to be an intrinsic factor that controls cortical size. Conditional deletion of Baf170 was found to promote indirect neurogenesis by increasing the pool of intermediate progenitors and in turn result in an enlarged cortex (34). Similarly, overexpression of Baf170 promoted direct neurogenesis and resulted in the development of a smaller cortex.…”