Summary
Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF subunit, ACTL6A, is amplified at an early stage in the development of squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads to its stoichiometric assembly into BAF complexes and drives its interaction and engagement with specific regulatory regions in the genome. In normal epithelial cells, ACTL6A was sub-stoichiometric to other BAF subunits. However, increased ACTL6A levels by ectopic expression or in SCC cells led to near-saturation of ACTL6A within BAF complexes. Increased ACTL6A occupancy enhanced polycomb opposition over the genome activating SCC genes and also enhanced the recruitment of transcription factor TEAD with its co-activator YAP, promoting their chromatin binding and enhancer accessibility. Both of these mechanisms appeared to be critical and function as a molecular AND gate for SCC initiation and maintenance, thereby explaining the specificity of the role of ACTL6A amplification in SCCs.
Highlights
ACTL6A occupancy within BAF complexes is sub-stoichiometric in normal epithelial cells.
SCC cells upregulate ACTL6A thus increasing ACTL6A assembly with BAF complexes.
Genome-wide chromatin profiling identifies ACTL6A-dependent regulatory regions.
Increasing ACTL6A incorporation enhances TEAD-YAP binding to BAF complexes.
ACTL6A overexpression counteracts polycomb-mediated repression at SCC signature genes.
Competing Interest Statement
G.R.C. is a founder and stockholder in Foghorn Therapeutics.
