The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis

Grant D. Barish, Ruth T. Yu, Malith S. Karunasiri, Diana Becerra, Jason Kim, Tiffany W. Tseng, Li Jung Tai, Matthias Leblanc, Cody Diehl, Leandro Cerchietti, Yury I. Miller, Joseph L. Witztum, Ari M. Melnick, Alexander L. Dent, Rajendra K. Tangirala, Ronald M. Evans

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Chronic inflammation is a hallmark of atherosclerosis, but its transcriptional underpinnings are poorly understood. We show that the transcriptional repressor Bcl6 is an anti-inflammatory regulator whose loss in bone marrow of Ldlr -/- mice results in severe atherosclerosis and xanthomatous tendonitis, a virtually pathognomonic complication in patients with familial hypercholesterolemia. Disruption of the interaction between Bcl6 and SMRT or NCoR with a peptide inhibitor in vitro recapitulated atherogenic gene changes in mice transplanted with Bcl6-deficient bone marrow, pointing to these cofactors as key mediators of Bcl6 inflammatory suppression. Using ChIP-seq, we reveal the SMRT and NCoR corepressor cistromes, each consisting of over 30,000 binding sites with a nearly 50% overlap. While the complete cistromes identify a diversity of signaling pathways, the Bcl6-bound subcistromes for each corepressor are highly enriched for NF-κB-driven inflammatory and tissue remodeling genes. These results reveal that Bcl6-SMRT/NCoR complexes constrain immune responses and contribute to the prevention of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)554-562
Number of pages9
JournalCell Metabolism
Volume15
Issue number4
DOIs
StatePublished - Apr 4 2012

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Barish, G. D., Yu, R. T., Karunasiri, M. S., Becerra, D., Kim, J., Tseng, T. W., Tai, L. J., Leblanc, M., Diehl, C., Cerchietti, L., Miller, Y. I., Witztum, J. L., Melnick, A. M., Dent, A. L., Tangirala, R. K., & Evans, R. M. (2012). The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis. Cell Metabolism, 15(4), 554-562. https://doi.org/10.1016/j.cmet.2012.02.012