Repression of PDGF-R-α after cellular injury involves TNF-α, formation of a c-Fos-YY1 complex, and negative regulation by HDAC

Zhang N, Chan CW, Sanchez-Guerrero E, Khachigian LM. Repression of PDGF-R-alpha after cellular injury involves TNF-alpha, formation of a c-Fos-YY1 complex, and negative regulation by HDAC. Am J Physiol Cell Physiol 302: C1590-C1598, 2012. First published February 8, 2012; doi:10.1152/ajpcell.00429.2011.-Wound healing is a complex dynamic process involving a variety of cell types, including fibroblasts that express and respond to cytokines and growth factors in the local microenvironment. The mechanisms controlling gene expression after injury at a transcriptional level are poorly understood. Here we show that decreased expression of a key receptor, PDGF-receptor (R)-alpha, after fibroblast injury is due to the release and paracrine activity of TNF-alpha. TNF-alpha inhibits PDGF-R-alpha expression and this involves formation of a c-Fos-Yin Yang 1 (YY1) complex and histone deacetylase (HDAC) activity. c-Fos, induced by TNF-alpha, negatively regulates PDGF-R-alpha transcription. Small interfering RNA ( siRNA) targeting c-Fos or the zinc finger transcription factor YY1 inhibits TNF-alpha suppression of PDGF-R-alpha expression. Coimmunoprecipitation studies show that TNF-alpha stimulates the formation of a complex between c-Fos with YY1. Furthermore, chromatin immunoprecipitation (ChIP) analysis reveals the enrichment of c-Fos, YY1, and HDAC-1 at the PDGF-R-alpha promoter in cells exposed to TNF-alpha. With suberoylanilide hydroxamic acid (SAHA) and HDAC-1 siRNA, we demonstrate that HDAC mediates TNF-alpha repression of PDGF-R-alpha. These findings demonstrate that transcriptional repression of PDGF-R-alpha after fibroblast injury involves paracrine activity of endogenous TNF-alpha, the formation of a c-Fos-YY1 complex, and negative regulatory activity by HDAC.