BRD4 mediates NF-?B-dependent epithelial-mesenchymal transition and pulmonary fibrosis via transcriptional elongation.

ABSTRACT: Chronic epithelial injury triggers a TGF-?-mediated cellular transition from normal epithelium into a mesenchymal-like state that produces subepithelial fibrosis and airway remodeling. Here we examined how TGF-? induces the mesenchymal cell state and determined its mechanism. We observed that TGF-? stimulation activates an inflammatory gene program controlled by the NF-?B/RelA signaling pathway. In the mesenchymal state, NF-?B-dependent immediate-early genes accumulate euchromatin marks and processive RNA polymerase. This program of immediate-early genes is activated by enhanced expression, nuclear translocation, and activating phosphorylation of the NF-?B/RelA transcription factor on Ser276, mediated by a paracrine signal. Phospho-Ser276 RelA binds to the BRD4/CDK9 transcriptional elongation complex, activating the paused RNA Pol II by phosphorylation on Ser2 in its carboxy-terminal domain. RelA-initiated transcriptional elongation is required for expression of the core epithelial-mesenchymal transition transcriptional regulators SNAI1, TWIST1, and ZEB1 and mesenchymal genes. Finally, we observed that pharmacological inhibition of BRD4 can attenuate experimental lung fibrosis induced by repetitive TGF-? challenge in a mouse model. These data provide a detailed mechanism for how activated NF-?B and BRD4 control epithelial-mesenchymal transition initiation and transcriptional elongation in model airway epithelial cells in vitro and in a murine pulmonary fibrosis model in vivo. Our data validate BRD4 as an in vivo target for the treatment of pulmonary fibrosis associated with inflammation-coupled remodeling in chronic lung diseases.

SUBMITTER: Tian B 

PROVIDER: S-EPMC5206405 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature