Recruitment of Brd3 and Brd4 to acetylated chromatin is essential for proinflammatory cytokine-induced matrix-degrading enzyme expression

Jin Dai, Sheng Zhou, Qiting Ge, Jinzhong Qin, Jianxin Li, Huangxian Ju, Yi Cao, Minghao Zheng, Chaojun Li, Xiang Gao, Huajian Teng, Qing Jiang

Research output: Contribution to journalArticle

Abstract

BackgroundProinflammatory cytokines, which can upregulate the expression of matrix-degrading enzymes in chondrocytes, play important roles in the development of osteoarthritis. BET family proteins, acting as the readers of acetylated modifications on histones, have been linked to transcriptional regulation. And a BET protein inhibitor, I-BET151, has been shown to inhibit the induction of matrix-degrading enzymes by proinflammatory cytokines in chondrocytes. Our objective is to clarify the role and mechanism of BET proteins on matrix-degrading enzyme gene expression by using a human chondrosarcoma cell line (SW1353).MethodsWe pretreated SW1353 cells with I-BET151 prior to treatment with IL-1 or TNF- and then checked the expression of four matrix-degrading enzyme genes (MMP1, MMP3, MMP13, and ADAMTS4). We performed knockdown of BET protein family members (BRD2, BRD3, and BRD4) with corresponding siRNAs in SW1353 cells prior to treatment with IL-1 or TNF- and checked the expression of the matrix-degrading enzyme genes. We evaluated Brd-mediated transcriptional regulation on the matrix-degrading enzyme genes by ChIP assay.ResultsWe confirmed that I-BET151 could suppress the IL-1- or TNF--induced expression of MMP1, MMP3, MMP13, and ADAMTS4 in SW1353 cells. Brd3 and Brd4 were required for the IL-1- or TNF--induced expression of matrix-degrading enzyme genes in SW1353 cells. We revealed that inducible acetylation of H4k5/8/12 and the recruitment of Brd3, Brd4, and p-TEFb to chromatin were involved in IL-1- or TNF--induced transcription.ConclusionsOur findings suggested that Brd3 and Brd4 were essential for the IL-1- or TNF--induced transcription of matrix-degrading enzyme genes, and recruitment of Brd3 and Brd4 to chromatin of these genes played the main role in this process.

Original languageEnglish
Article number59
Number of pages10
JournalJournal of Orthopaedic Surgery and Research
Volume14
DOIs
Publication statusPublished - 20 Feb 2019

Cite this

Dai, Jin ; Zhou, Sheng ; Ge, Qiting ; Qin, Jinzhong ; Li, Jianxin ; Ju, Huangxian ; Cao, Yi ; Zheng, Minghao ; Li, Chaojun ; Gao, Xiang ; Teng, Huajian ; Jiang, Qing. / Recruitment of Brd3 and Brd4 to acetylated chromatin is essential for proinflammatory cytokine-induced matrix-degrading enzyme expression. In: Journal of Orthopaedic Surgery and Research. 2019 ; Vol. 14.
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title = "Recruitment of Brd3 and Brd4 to acetylated chromatin is essential for proinflammatory cytokine-induced matrix-degrading enzyme expression",
abstract = "BackgroundProinflammatory cytokines, which can upregulate the expression of matrix-degrading enzymes in chondrocytes, play important roles in the development of osteoarthritis. BET family proteins, acting as the readers of acetylated modifications on histones, have been linked to transcriptional regulation. And a BET protein inhibitor, I-BET151, has been shown to inhibit the induction of matrix-degrading enzymes by proinflammatory cytokines in chondrocytes. Our objective is to clarify the role and mechanism of BET proteins on matrix-degrading enzyme gene expression by using a human chondrosarcoma cell line (SW1353).MethodsWe pretreated SW1353 cells with I-BET151 prior to treatment with IL-1 or TNF- and then checked the expression of four matrix-degrading enzyme genes (MMP1, MMP3, MMP13, and ADAMTS4). We performed knockdown of BET protein family members (BRD2, BRD3, and BRD4) with corresponding siRNAs in SW1353 cells prior to treatment with IL-1 or TNF- and checked the expression of the matrix-degrading enzyme genes. We evaluated Brd-mediated transcriptional regulation on the matrix-degrading enzyme genes by ChIP assay.ResultsWe confirmed that I-BET151 could suppress the IL-1- or TNF--induced expression of MMP1, MMP3, MMP13, and ADAMTS4 in SW1353 cells. Brd3 and Brd4 were required for the IL-1- or TNF--induced expression of matrix-degrading enzyme genes in SW1353 cells. We revealed that inducible acetylation of H4k5/8/12 and the recruitment of Brd3, Brd4, and p-TEFb to chromatin were involved in IL-1- or TNF--induced transcription.ConclusionsOur findings suggested that Brd3 and Brd4 were essential for the IL-1- or TNF--induced transcription of matrix-degrading enzyme genes, and recruitment of Brd3 and Brd4 to chromatin of these genes played the main role in this process.",
keywords = "Matrix-degrading enzymes, Brd, Transcription, Acetylation, BROMODOMAIN PROTEIN BRD4, HISTONE DEACETYLASE 3, RNA-POLYMERASE-II, GENE-EXPRESSION, TRANSCRIPTIONAL REGULATION, P-TEFB, CHONDROCYTES, INVOLVEMENT, INHIBITION, ELONGATION",
author = "Jin Dai and Sheng Zhou and Qiting Ge and Jinzhong Qin and Jianxin Li and Huangxian Ju and Yi Cao and Minghao Zheng and Chaojun Li and Xiang Gao and Huajian Teng and Qing Jiang",
year = "2019",
month = "2",
day = "20",
doi = "10.1186/s13018-019-1091-3",
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journal = "Journal of Orthopaedic Surgery and Research",
issn = "1749-799X",
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Recruitment of Brd3 and Brd4 to acetylated chromatin is essential for proinflammatory cytokine-induced matrix-degrading enzyme expression. / Dai, Jin; Zhou, Sheng; Ge, Qiting; Qin, Jinzhong; Li, Jianxin; Ju, Huangxian; Cao, Yi; Zheng, Minghao; Li, Chaojun; Gao, Xiang; Teng, Huajian; Jiang, Qing.

In: Journal of Orthopaedic Surgery and Research, Vol. 14, 59, 20.02.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Recruitment of Brd3 and Brd4 to acetylated chromatin is essential for proinflammatory cytokine-induced matrix-degrading enzyme expression

AU - Dai, Jin

AU - Zhou, Sheng

AU - Ge, Qiting

AU - Qin, Jinzhong

AU - Li, Jianxin

AU - Ju, Huangxian

AU - Cao, Yi

AU - Zheng, Minghao

AU - Li, Chaojun

AU - Gao, Xiang

AU - Teng, Huajian

AU - Jiang, Qing

PY - 2019/2/20

Y1 - 2019/2/20

N2 - BackgroundProinflammatory cytokines, which can upregulate the expression of matrix-degrading enzymes in chondrocytes, play important roles in the development of osteoarthritis. BET family proteins, acting as the readers of acetylated modifications on histones, have been linked to transcriptional regulation. And a BET protein inhibitor, I-BET151, has been shown to inhibit the induction of matrix-degrading enzymes by proinflammatory cytokines in chondrocytes. Our objective is to clarify the role and mechanism of BET proteins on matrix-degrading enzyme gene expression by using a human chondrosarcoma cell line (SW1353).MethodsWe pretreated SW1353 cells with I-BET151 prior to treatment with IL-1 or TNF- and then checked the expression of four matrix-degrading enzyme genes (MMP1, MMP3, MMP13, and ADAMTS4). We performed knockdown of BET protein family members (BRD2, BRD3, and BRD4) with corresponding siRNAs in SW1353 cells prior to treatment with IL-1 or TNF- and checked the expression of the matrix-degrading enzyme genes. We evaluated Brd-mediated transcriptional regulation on the matrix-degrading enzyme genes by ChIP assay.ResultsWe confirmed that I-BET151 could suppress the IL-1- or TNF--induced expression of MMP1, MMP3, MMP13, and ADAMTS4 in SW1353 cells. Brd3 and Brd4 were required for the IL-1- or TNF--induced expression of matrix-degrading enzyme genes in SW1353 cells. We revealed that inducible acetylation of H4k5/8/12 and the recruitment of Brd3, Brd4, and p-TEFb to chromatin were involved in IL-1- or TNF--induced transcription.ConclusionsOur findings suggested that Brd3 and Brd4 were essential for the IL-1- or TNF--induced transcription of matrix-degrading enzyme genes, and recruitment of Brd3 and Brd4 to chromatin of these genes played the main role in this process.

AB - BackgroundProinflammatory cytokines, which can upregulate the expression of matrix-degrading enzymes in chondrocytes, play important roles in the development of osteoarthritis. BET family proteins, acting as the readers of acetylated modifications on histones, have been linked to transcriptional regulation. And a BET protein inhibitor, I-BET151, has been shown to inhibit the induction of matrix-degrading enzymes by proinflammatory cytokines in chondrocytes. Our objective is to clarify the role and mechanism of BET proteins on matrix-degrading enzyme gene expression by using a human chondrosarcoma cell line (SW1353).MethodsWe pretreated SW1353 cells with I-BET151 prior to treatment with IL-1 or TNF- and then checked the expression of four matrix-degrading enzyme genes (MMP1, MMP3, MMP13, and ADAMTS4). We performed knockdown of BET protein family members (BRD2, BRD3, and BRD4) with corresponding siRNAs in SW1353 cells prior to treatment with IL-1 or TNF- and checked the expression of the matrix-degrading enzyme genes. We evaluated Brd-mediated transcriptional regulation on the matrix-degrading enzyme genes by ChIP assay.ResultsWe confirmed that I-BET151 could suppress the IL-1- or TNF--induced expression of MMP1, MMP3, MMP13, and ADAMTS4 in SW1353 cells. Brd3 and Brd4 were required for the IL-1- or TNF--induced expression of matrix-degrading enzyme genes in SW1353 cells. We revealed that inducible acetylation of H4k5/8/12 and the recruitment of Brd3, Brd4, and p-TEFb to chromatin were involved in IL-1- or TNF--induced transcription.ConclusionsOur findings suggested that Brd3 and Brd4 were essential for the IL-1- or TNF--induced transcription of matrix-degrading enzyme genes, and recruitment of Brd3 and Brd4 to chromatin of these genes played the main role in this process.

KW - Matrix-degrading enzymes

KW - Brd

KW - Transcription

KW - Acetylation

KW - BROMODOMAIN PROTEIN BRD4

KW - HISTONE DEACETYLASE 3

KW - RNA-POLYMERASE-II

KW - GENE-EXPRESSION

KW - TRANSCRIPTIONAL REGULATION

KW - P-TEFB

KW - CHONDROCYTES

KW - INVOLVEMENT

KW - INHIBITION

KW - ELONGATION

U2 - 10.1186/s13018-019-1091-3

DO - 10.1186/s13018-019-1091-3

M3 - Article

VL - 14

JO - Journal of Orthopaedic Surgery and Research

JF - Journal of Orthopaedic Surgery and Research

SN - 1749-799X

M1 - 59

ER -