1. The Bcl6-SMRT/NCoR Cistrome Represses Inflammation to Attenuate Atherosclerosis.
- Author
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Barish, Grant D., Yu, Ruth T., Karunasiri, Malith S., Becerra, Diana, Kim, Jason, Tseng, Tiffany W., Tai, Li-Jung, LeBlanc, Matthias, Diehl, Cody, Cerchietti, Leandro, Miller, Yury I., Witztum, Joseph L., Melnick, Ari M., Dent, Alexander L., Tangirala, Rajendra K., and Evans, Ronald M.
- Subjects
ATHEROSCLEROSIS ,INFLAMMATION ,HYPERCHOLESTEREMIA ,TRANSCRIPTION factors ,CELLULAR signal transduction ,IMMUNE response ,LABORATORY mice ,BONE marrow - Abstract
Summary: 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. [ABSTRACT FROM AUTHOR]- Published
- 2012
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