Gβγ subunits colocalize with RNA polymerase II and regulate transcription in cardiac fibroblasts

Gβγ subunits mediate many different signaling processes in various compartments of the cell, including the nucleus. To gain insight into the functions of nuclear Gβγ signaling, we investigated the functional role of Gβγ signaling in the regulation of GPCR-mediated gene expression in primary rat neonatal cardiac fibroblasts. We identified a novel, negative, regulatory role for the Gβ₁γ dimer in the fibrotic response. Depletion of Gβ₁ led to derepression of the fibrotic response at the mRNA and protein levels under basal conditions and an enhanced fibrotic response after sustained stimulation of the angiotensin II type I receptor. Our genome-wide chromatin immunoprecipitation experiments revealed that Gβ₁ colocalized and interacted with RNA polymerase II on fibrotic genes in an angiotensin II-dependent manner. Additionally, blocking transcription with inhibitors of Cdk9 prevented association of Gβγ with transcription complexes. Together, our findings suggest that Gβ₁γ is a novel transcriptional regulator of the fibrotic response that may act to restrict fibrosis to conditions of sustained fibrotic signaling. Our work expands the role for Gβγ signaling in cardiac fibrosis and may have broad implications for the role of nuclear Gβγ signaling in other cell types.