David Klein - Hainer Lab
"Identifying an BAF-driven mechanism of enhancer regulation in acute myeloid leukemia."
Friday, February 5, 2021
12:10 PM
Virtual Zoom seminar
Abstract:
The mammalian SWI/SNF complex homolog BAF critically regulates gene expression to oversee development, cell fate decisions, and tumor suppression. BAF complex members are mutated in approximately 23% of human cancers, with multiple known driver mutations. Recently, a novel variant BAF complex (GBAF) was characterized, defined in part by the presence of the bromodomain-containing subunit BRD9. Through this bromodomain, BRD9 acts as a reader of acetylated lysine residues that generally mark accessible regions of DNA, such as enhancers. Using a small molecule inhibitor of the BRD9 bromodomain (I-BRD9), I have identified a role for BRD9 in regulating GBAF complex localization to chromatin at enhancers throughout the human genome. Through this enhancer binding, GBAF maintains expression of the MYC master blood transcription factor. MYC and BRD9 are both overexpressed in many patients with acute myeloid leukemia (AML), and ectopic MYC expression alone is sufficient to drive leukemia onset and progression. While MYC is an interesting candidate for leukemia progression, it is just one of many lineage-determining factors that are regulated by cis-regulatory elements, which themselves may be regulated by the GBAF complex. To identify the extent of this regulation, I have treated AML and wildtype myeloid cell lines with I-BRD9, followed by genome-wide analysis of GBAF subunit chromatin binding, nascent RNA sequencing, and analysis of nucleosome positioning. My work aims to identify a GBAF-based gene regulatory pathway acting through maintenance of nucleosome occupancy and positioning at cis-regulatory elements.