Gαq-Stimulated Gene Expression Is Insensitive to Bromo Extra Terminal Domain Inhibitors in HEK 293 Cells

Bromodomain and extraterminal domain (BET) family proteins are ubiquitous transcriptional co-activators that function broadly in cellular differentiation, proliferation, and stress responses. Pharmacological inhibition of BET proteins with small molecules that disrupt bromodomain engagement with acetyllysine residues (such as JQ1) or drive their degradation through the ubiquitin-proteasome system (such as dBET6) ameliorates pathological gene expression in a range of systems and shows promise as a potential therapeutic strategy. Understanding the cell-type and signaling pathway requirements that dictate BET dependence in a particular cellular context remains incomplete. We previously demonstrated that, in neonatal rat cardiomyocytes, GPCR-induced hypertrophy responses depended strongly on the BET protein Brd4 when signaling was coupled to Gαs, but not Gαq. Here, we tested whether Brd4 was differentially responsive to G protein isoforms in HEK 293 cells by expressing Gαs- or Gαq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Gαq induced the expression of a group of early response genes and inflammatory genes in a manner largely insensitive to pharmacological BET inhibition, consistent with our previous data in cardiomyocytes. Gαs activated a small subset of the Gαq-induced genes, but this effect was largely reversed by dBET6. Our data further suggest that there may be general signaling requirements to activate Brd4 across cell types.