Pan-SMARCA/PB1 Bromodomain Inhibitors and Their Role in Regulating Adipogenesis

Accessibility
of the human genome is modulated by the ATP-driven
SWI/SNF chromatin remodeling multiprotein complexes BAF (BRG1/BRM-associated
factor) and PBAF (polybromo-associated BAF factor), which involves
reading of acetylated histone tails by the bromodomain-containing
proteins SMARCA2 (BRM), SMARCA4 (BRG1), and polybromo-1. Dysregulation
of chromatin remodeling leads to aberrant cell proliferation and differentiation.
Here, we have characterized a set of potent and cell-active bromodomain
inhibitors with pan-selectivity for canonical family VIII bromodomains.
Targeted SWI/SNF bromodomain inhibition blocked the expression of
key genes during adipogenesis, including the transcription factors
PPARγ and C/EBPα, and impaired the differentiation of
3T3-L1 murine fibroblasts into adipocytes. Our data highlight the
role of SWI/SNF bromodomains in adipogenesis and provide a framework
for the development of SWI/SNF bromodomain inhibitors for indirect
targeting of key transcription factors regulating cell differentiation.