A2b adenosine signaling represses CIITA transcription via an epigenetic mechanism in vascular smooth muscle cells

Jun Xia, Mingming Fang, Xiaoyan Wu, Yuyu Yang, Liming Yu, Huihui Xu, Hui Kong, Qi Tan, Hong Wang, Weiping Xie, Yong Xu

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Chronic inflammation plays a major role in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMC), by expressing and presenting major histocompatibility complex II (MHC II) molecules, help recruit T lymphocyte and initiate the inflammatory response within the vasculature. We have previously shown that VSMCs isolated from mice with deficient adenosine A2b receptor (A2b-null) exhibit higher expression of class II transactivator (CIITA), the master regulator of MHC II transcription, compared to wild type littermates. Here we report that activation of A2b adenosine signaling suppresses CIITA expression in human aortic smooth muscle cells. Down-regulation of CIITA expression was largely attributable to transcriptional repression of type III and IV promoters. Chromatin immunoprecipitation (ChIP) analyses revealed that A2b signaling repressed CIITA transcription by attenuating specific histone modifications on the CIITA promoters in a STAT1-dependent manner. STAT1 interacted with PCAF/GCN5, histone H3K9 acetyltransferases, and WDR5, a key component of the mammalian H3K4 methyltransferase complex, to activate CIITA transcription. A2b signaling prevented recruitment of PCAF/GCN5 and WDR5 to the CIITA promoters in a STAT1-dependent manner. In conclusion, our data suggest that adenosine A2b signaling represses CIITA transcription in VSMCs by manipulating the interaction between STAT1 and the epigenetic machinery.

Original languageEnglish (US)
Pages (from-to)665-676
Number of pages12
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1849
Issue number6
DOIs
StatePublished - May 15 2015
Externally publishedYes

Keywords

  • Adenosine A2b signaling
  • CIITA transcription
  • PCAF/GCN5
  • STAT1
  • VSMC
  • WDR5

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biophysics
  • Structural Biology
  • Biochemistry

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