An interaction between Gβγ and RNA polymerase II regulates transcription in cardiac fibroblasts

Gβγ subunits are involved in an array of different signalling processes in various compartments of the cell, including the nucleus. To gain further insight into the functions of nuclear Gβγ, we investigated the functional role of Gβγ signalling in the regulation of GPCR-mediated gene expression in primary rat neonatal cardiac fibroblasts. Here, we demonstrate that following activation of the angiotensin II type I receptor in these cells, Gβγ dimers interact with RNA polymerase II (RNAPII). Our findings suggest that Gβ1 recruitment to RNAPII negatively regulates the fibrotic transcriptional response, which can be overcome by strong fibrotic stimuli. The Gβγ-RNAPII interaction was also investigated in HEK 293 cells and was regulated by signaling pathways that diverged from those operating in cardiac fibroblasts, suggesting that although it may be a conserved feature of transcriptional regulation, such regulation may be cell-specific. Taken together, our studies reveal a novel interaction between Gβγ subunits and RNA polymerase II and expand the role for Gβγ signalling in cardiac fibrosis. Gβ1 and RNAPII ChIP-seq from neonatal rat cardiac fibroblasts

Gβγ亚基参与细胞不同亚细胞区域（包括细胞核）内的多种信号转导过程。为深入解析细胞核内Gβγ的功能，我们探究了Gβγ信号转导在原代新生大鼠心脏成纤维细胞中调控G蛋白偶联受体（G protein-coupled receptor，GPCR）介导基因表达的功能性作用。本研究证实，在该类细胞中激活血管紧张素II 1型受体后，Gβγ二聚体可与RNA聚合酶II（RNA polymerase II，RNAPII）发生相互作用。研究结果显示，Gβ1招募至RNA聚合酶II可负向调控纤维化转录应答，且该调控效应可被强纤维化刺激所抵消。我们还在HEK 293细胞中探究了Gβγ-RNA聚合酶II的相互作用，其调控信号通路与心脏成纤维细胞中的调控通路存在差异，这表明尽管该相互作用可能是转录调控的保守特征，但此类调控机制可能具有细胞特异性。综上，本研究揭示了Gβγ亚基与RNA聚合酶II之间的新型相互作用，并拓展了Gβγ信号转导在心脏纤维化中的功能范畴。本数据集包含新生大鼠心脏成纤维细胞的Gβ1与RNA聚合酶II染色质免疫沉淀测序（Chromatin Immunoprecipitation sequencing，ChIP-seq）数据。