BAF complexes maintain accessibility at stimulus-responsive chromatin and are required for transcriptional stimulus responses [RNA-seq]

We found that several TFs were associated with sensitivity to BAF inhibition, including widely expressed Activator Protein 1 (AP-1) factors and lymphoid lineage-defining TFs such as RUNX3 and PU.1. Surprisingly, we also found that cREs bearing the chromatin signature of “primed” enhancers – characterized by H3K4me1 enrichment in the absence of the “active” enhancer mark H3K27ac – were significantly more sensitive to BAF inhibition than typical active enhancers.

Nearly all primed enhancers lost chromatin accessibility within 30 minutes of BAF inhibition. Notably, primed enhancers are known to facilitate transcriptional responses to external stimuli. Thus, we reasoned that BAF function may be required for cells to mount transcriptional stimulus responses.

To test this theory, we assessed the effect of acute BAF inhibition on responses to two orthogonal stimuli, interferon gamma and dexamethasone. We found that BAF inhibition was sufficient to prevent chromatin and transcriptional responses to these stimuli. cREs which normally gained accessibility in response to stimulation failed to do so with BAF inhibition, and these cREs were linked to genes with suppressed transcriptional induction upon stimulation.

Collectively, our results demonstrate a requirement for continuous BAF activity to enable stimulus response and suggest that defective signal responsiveness may be a pathogenic mechanism in disease states caused by loss-of-function mutations in BAF subunits.