HRP2-DPF3a-BAF complex coordinates histone modification and chromatin remodeling to regulate myogenic gene transcription [ATAC-Seq]

Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we demonstrate that HRP2-DPF3a-BAF complex coordinates histone H3 lysine 36 methylation (H3K36me) and ATP-dependent chromatin remodeling to regulate chromatin dynamic and gene transcription during myogenic differentiation. Mechanistically, through its HIV integrase binding domain (IBD), HRP2 associates with BRG1/BRM associated factor (BAF) chromatin remodeling complex by direct interaction with BAF45c (DPF3a) subunit. Through its Pro-Trp-Trp-Pro (PWWP) domain, HRP2 preferentially binds to H3K36me2. Integrative transcriptomic and cistromic analyses, coupled with ATAC-seq, reveal that HRP2 and DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of BRG1, the ATPase subunit of the BAF complex. Overall design: ATAC-seq analysis from C2C12 transfected with siRNAs against Hrp2/Dpf3a or control 24h before start of differentiation. Cells were harvested for chromatin accessibility profiling after 48h of differentiation in differentiation medium. Two replicates were performed per siRNA.