title: The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis.
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.
authors.affiliation: Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.forename: Malith S
authors.initials: MS
authors.lastname: Karunasiri
authors.forename: Diana
authors.initials: D
authors.lastname: Becerra
authors.forename: Jason
authors.initials: J
authors.lastname: Kim
authors.forename: Tiffany W
authors.initials: TW
authors.lastname: Tseng
authors.forename: Li-Jung
authors.initials: LJ
authors.lastname: Tai
authors.forename: Matthias
authors.initials: M
authors.lastname: Leblanc
authors.forename: Cody
authors.initials: C
authors.lastname: Diehl
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Yury I
authors.initials: YI
authors.lastname: Miller
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Dent
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Tangirala
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D001483:Base Sequence; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D052256:Tendinopathy / Q000473:pathology
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D051560:Proto-Oncogene Proteins c-bcl-6; C099252:oxidized low density lipoprotein; D002784:Cholesterol