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Cell Metab. 2012 Apr 4;15(4):554-62. doi: 10.1016/j.cmet.2012.02.012. Epub 2012 Mar 29.

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

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1
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

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.

PMID:
22465074
PMCID:
PMC3367511
DOI:
10.1016/j.cmet.2012.02.012
[Indexed for MEDLINE]
Free PMC Article

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