The BcI6-SMRT/NCoR Cistrome Represses Inflammation to Attenuate Atherosclerosis

被引：101

作者：

Barish, Grant D. ^{[2
,3
]}

Yu, Ruth T. ^{[2
,3
]}

Karunasiri, Malith S. ^{[2
,3
]}

Becerra, Diana ^{[1
]}

Kim, Jason ^{[1
]}

Tseng, Tiffany W. ^{[2
,3
]}

Tai, Li-Jung ^{[2
,3
]}

LeBlanc, Matthias ^{[2
,3
]}

Diehl, Cody ^{[4
]}

Cerchietti, Leandro ^{[5
]}

Miller, Yury I. ^{[4
]}

Witztum, Joseph L. ^{[4
]}

Melnick, Ari M. ^{[5
]}

Dent, Alexander L. ^{[6
]}

Tangirala, Rajendra K. ^{[1
]}

Evans, Ronald M. ^{[2
,3
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA

[2] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA

[3] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA

[4] Univ Calif San Diego, Dept Med, Div Endocrinol & Metab, La Jolla, CA 92093 USA

[5] Weill Cornell Med Coll, Dept Med, Div Hematol Oncol, New York, NY 10065 USA

[6] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA

来源：

CELL METABOLISM | 2012年 / 15卷 / 04期

基金：

美国国家卫生研究院;

关键词：

GERMINAL-CENTER FORMATION; ACCELERATED ATHEROSCLEROSIS; BCL-6; GENE; MACROPHAGE; MICE; TRANSCRIPTION; INHIBITION; ACTIVATION; EXPRESSION;

D O I：

10.1016/j.cmet.2012.02.012

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Chronic inflammation is a hallmark of atherosclerosis, but its transcriptional underpinnings are poorly understood. We show that the transcriptional repressor BcI6 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 BcI6 and SMRT or NCoR with a peptide inhibitor in vitro recapitulated atherogenic gene changes in mice transplanted with BcI6-deficient bone marrow, pointing to these cofactors as key mediators of BcI6 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 BcI6-bound subcistromes for each corepressor are highly enriched for NF-kappa B-driven inflammatory and tissue remodeling genes. These results reveal that BcI6-SMRT/NCoR complexes constrain immune responses and contribute to the prevention of atherosclerosis.

引用

页码：554 / 562

页数：9

共 27 条

[1] Transcription factor and kinase-mediated signaling in atherosclerosis and vascular injury [J].

Adhikari N. ;

Charles N. ;

Lehmann U. ;

Hall J.L. .

Current Atherosclerosis Reports, 2006, 8 (3) :252-260

[2] Role of platelet-derived growth factors in physiology and medicine [J].

Andrae, Johanna ;

Gallini, Radiosa ;

Betsholtz, Christer .

GENES & DEVELOPMENT, 2008, 22 (10) :1276-1312

[3] Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response [J].

Barish, Grant D. ;

Yu, Ruth T. ;

Karunasiri, Malith ;

Ocampo, Corinne B. ;

Dixon, Jesse ;

Benner, Chris ;

Dent, Alexander L. ;

Tangirala, Rajendra K. ;

Evans, Ronald M. .

GENES & DEVELOPMENT, 2010, 24 (24) :2760-2765

[4] BCL6: Master Regulator of the Germinal Center Reaction and Key Oncogene in B Cell Lymphomagenesis [J].

Basso, Katia ;

Dalla-Favera, Riccardo .

ADVANCES IN IMMUNOLOGY, VOL 105, 2010, 105 :193-210

[5] A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo [J].

Cerchietti, Leandro C. ;

Yang, Shao Ning ;

Shaknovich, Rita ;

Hatzi, Katerina ;

Polo, Jose M. ;

Chadburn, Amy ;

Dowdy, Steven F. ;

Melnick, Ari .

BLOOD, 2009, 113 (15) :3397-3405

[6] Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene mutation [J].

Civeira, F ;

Castillo, S ;

Alonso, R ;

Meriño-Ibarra, E ;

Cenarro, A ;

Artied, M ;

Martín-Fuentes, P ;

Ros, E ;

Pocoví, M ;

Mata, P .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (09) :1960-1965

[7] Macrophage-targeted overexpression of urokinase causes accelerated atherosclerosis, coronary artery occlusions, and premature death [J].

Cozen, AE ;

Moriwaki, H ;

Kremen, M ;

DeYoung, MB ;

Dichek, HL ;

Slezicki, KI ;

Young, SG ;

Véniant, M ;

Dichek, DA .

CIRCULATION, 2004, 109 (17) :2129-2135

[8] Nuclear factor κB signaling in atherogenesis [J].

de Winther, MPJ ;

Kanters, E ;

Kraal, G ;

Hofker, MH .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (05) :904-914

[9] Control of inflammation, cytokine expression, and germinal center formation by BCL-6 [J].

Dent, AL ;

Shaffer, AL ;

Yu, X ;

Allman, D ;

Staudt, LM .

SCIENCE, 1997, 276 (5312) :589-592

[10] Endothelial Cell-Specific NF-κB Inhibition Protects Mice from Atherosclerosis [J].

Gareus, Ralph ;

Kotsaki, Elena ;

Xanthoulea, Sofia ;

van der Made, Ingelborg ;

Gijbels, Marion J. J. ;

Kardakaris, Rozina ;

Polykratis, Apostolos ;

Kollias, George ;

de Winther, Menno P. J. ;

Pasparakis, Manolis .

CELL METABOLISM, 2008, 8 (05) :372-383

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