Abstract
The role of individual subunits in the targeting and function of the mammalian BRG1-associated factors (BAF) complex in embryonic stem cell (ESC) pluripotency maintenance has not yet been elucidated. Here we find that the Bromodomain containing protein 9 (BRD9) and Glioma tumor suppressor candidate region gene 1 (GLTSCR1) or its paralog GLTSCR1-like (GLTSCR1L) define a smaller, non-canonical BAF complex (GBAF complex) in mouse ESCs that is distinct from the canonical ESC BAF complex (esBAF). GBAF and esBAF complexes are targeted to different genomic features, with GBAF co-localizing with key regulators of naive pluripotency, which is consistent with its specific function in maintaining naive pluripotency gene expression. BRD9 interacts with BRD4 in a bromodomain-dependent fashion, which leads to the recruitment of GBAF complexes to chromatin, explaining the functional similarity between these epigenetic regulators. Together, our results highlight the biological importance of BAF complex heterogeneity in maintaining the transcriptional network of pluripotency.
Highlights
The role of individual subunits in the targeting and function of the mammalian BRG1associated factors (BAF) complex in embryonic stem cell (ESC) pluripotency maintenance has not yet been elucidated
Gene set enrichment analysis (GSEA) showed that I-Bromodomain containing protein 9 (BRD9)-downregulated genes are positively enriched among genes that decrease upon Brd[9] knockdown, while I-BRD9-upregulated genes are enriched among genes that increase upon Brd[9] knockdown (Fig. 1g)
These data indicate that BRD9 and BRG1 cooperate to regulate a subset of genes in ESCs that are critical for ESC maintenance
Summary
The role of individual subunits in the targeting and function of the mammalian BRG1associated factors (BAF) complex in embryonic stem cell (ESC) pluripotency maintenance has not yet been elucidated. To maintain ESC identity, the genome is precisely controlled so that only stem cell-specific transcription programs are turned on while lineagespecific programs are silenced[1,2] This control is in part achieved by ATP-dependent chromatin remodeling complexes, which regulate chromatin structure[3,4]. We provide evidence for BD and extra-terminal protein 4 (BRD4)-mediated targeting of the GBAF complex that is BD-dependent, which accounts for their complementary roles in regulating the naive pluripotency transcriptional network. Our studies provide important insight into BRD9 function and add to our understanding of how diversity in BAF complex assembly contributes to the intricate control of the ESC transcription program
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