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 Dent, Rajendra K. Tangirala, Ronald M. Evans

Research output: Contribution to journalArticle

62 Citations (Scopus)

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

Fingerprint

Atherosclerosis
Inflammation
Nuclear Receptor Co-Repressor 2
Bone Marrow
Co-Repressor Proteins
Tendinopathy
Hyperlipoproteinemia Type II
Antigen-Antibody Complex
Genes
Anti-Inflammatory Agents
Binding Sites
Peptides
In Vitro Techniques

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Barish, G. D., Yu, R. T., Karunasiri, M. S., Becerra, D., Kim, J., Tseng, T. W., ... 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

The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis. / 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; Tangirala, Rajendra K.; Evans, Ronald M.

In: Cell Metabolism, Vol. 15, No. 4, 04.04.2012, p. 554-562.

Research output: Contribution to journalArticle

Barish, GD, Yu, RT, Karunasiri, MS, Becerra, D, Kim, J, Tseng, TW, Tai, LJ, Leblanc, M, Diehl, C, Cerchietti, L, Miller, YI, Witztum, JL, Melnick, AM, Dent, A, Tangirala, RK & Evans, RM 2012, 'The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis', Cell Metabolism, vol. 15, no. 4, pp. 554-562. https://doi.org/10.1016/j.cmet.2012.02.012
Barish GD, Yu RT, Karunasiri MS, Becerra D, Kim J, Tseng TW et al. The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis. Cell Metabolism. 2012 Apr 4;15(4):554-562. https://doi.org/10.1016/j.cmet.2012.02.012
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 ; Tangirala, Rajendra K. ; Evans, Ronald M. / The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis. In: Cell Metabolism. 2012 ; Vol. 15, No. 4. pp. 554-562.
@article{61bea3a2daa9400daf67fd82d71424e8,
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.",
author = "Barish, {Grant D.} and Yu, {Ruth T.} and Karunasiri, {Malith S.} and Diana Becerra and Jason Kim and Tseng, {Tiffany W.} and Tai, {Li Jung} and Matthias Leblanc and Cody Diehl and Leandro Cerchietti and Miller, {Yury I.} and Witztum, {Joseph L.} and Melnick, {Ari M.} and Alexander Dent and Tangirala, {Rajendra K.} and Evans, {Ronald M.}",
year = "2012",
month = "4",
day = "4",
doi = "10.1016/j.cmet.2012.02.012",
language = "English",
volume = "15",
pages = "554--562",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

T1 - The Bcl6-SMRT/NCoR cistrome represses inflammation to attenuate atherosclerosis

AU - Barish, Grant D.

AU - Yu, Ruth T.

AU - Karunasiri, Malith S.

AU - Becerra, Diana

AU - Kim, Jason

AU - Tseng, Tiffany W.

AU - Tai, Li Jung

AU - Leblanc, Matthias

AU - Diehl, Cody

AU - Cerchietti, Leandro

AU - Miller, Yury I.

AU - Witztum, Joseph L.

AU - Melnick, Ari M.

AU - Dent, Alexander

AU - Tangirala, Rajendra K.

AU - Evans, Ronald M.

PY - 2012/4/4

Y1 - 2012/4/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84859450495&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859450495&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2012.02.012

DO - 10.1016/j.cmet.2012.02.012

M3 - Article

C2 - 22465074

AN - SCOPUS:84859450495

VL - 15

SP - 554

EP - 562

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 4

ER -