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Smarcb1 is indispensable for the nervous system development and its loss results in a deregulation of esBAF binding [ChIP-seq]

ABSTRACT: Using ChIP-seq technology, we aimed to provide insight into the consequences of the knockdown of Smarcb1, an essential esBAF subunit, for the binding of the esBAF complex (Smarca4), the PRC2 complex (Ezh2) as well as for histone marks H3K27me3, H3K27ac and H3K4me3. We show that Smarcb1 knockdown results in the change of BAF complex binding in both directions: decreased binding (potentially by loss of function) as well as increased binding (potentially by retargeting). Furthermore, we see that binding changes especially occur in regions important for basic cellular functions (adhesion, cell organization, metabolism) as well as regions crucial for development (especially nervous system development). In addition, we depicted binding changes in enhancer regions in which a decrease of BAF binding was much more prominent than in gene regions.

ORGANISM(S): Mus musculus

PROVIDER: GSE186667 | GEO | 2022/04/27

REPOSITORIES: GEO

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Project description:The mammalian BRG1-associated factors (BAF) complex is a multi-subunit chromatin remodeling complex that is an important component of the embryonic stem cell (ESC) transcriptional regulatory network. However, the role of individual subunits in BAF complex targeting and function needs to be elucidated. Here, we find that the Bromodomain containing protein 9 (BRD9) and Glioma tumor suppressor candidate region gene 1 (GLTSCR1; also known as BICRA) or its paralog GLTSCR1-like (also known as BICRAL) define a smaller, non-canonical BAF complex (GBAF for GLTSCR1/1L-containing BAF complex) in mouse ESCs that is distinct from the canonical embryonic stem cell BAF (esBAF) and the polybromo-associated BAF (PBAF) complexes. GBAF lacks several esBAF subunits, including BAF47, BAF57 and ARID1A. We demonstrate that GBAF and esBAF complexes are targeted to different features of the genome and are co-bound with different sets of pluripotency transcription factors. Specifically, GBAF complexes co-localize with key regulators of naïve pluripotency, KLF4 and Sp5, on the genome. Consistent with this, we provide evidence that GBAF's specific function is to regulate the transcription of genes involved in the maintenance of naïve pluripotency, including Nanog and Prdm14. Additionally, we show that BRD9 is displaced from chromatin by the selective BRD9 bromodomain inhibitor, I-BRD9, and that this leads to changes in target gene expression. The function of the GBAF complex in ESCs is highly correlated with the function of BRD4, consistent with an association between GBAF complexes and BRD4. We find that GBAF complexes are directly recruited to chromatin by BRD4 in a bromodomain-dependent fashion and we identify a set of I-BRD9- and JQ1-sensitive BRD9 binding sites that determine the functional similarity between these epigenetic regulators. Together, our results demonstrate functionally specific roles for BAF complex assemblies in maintaining the transcriptional network of pluripotency, highlighting the biological importance of complex heterogeneity.

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Smarcb1 is indispensable for the nervous system development and its loss results in a deregulation of esBAF binding [ChIP-seq]

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