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

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Abstract

Background

Proinflammatory 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).

Methods

We pretreated SW1353 cells with I-BET151 prior to treatment with IL-1β or TNF-α 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-1β or TNF-α 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.

Results

We confirmed that I-BET151 could suppress the IL-1β- or TNF-α-induced expression of MMP1, MMP3, MMP13, and ADAMTS4 in SW1353 cells. Brd3 and Brd4 were required for the IL-1β- or TNF-α-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-1β- or TNF-α-induced transcription.

Conclusions

Our findings suggested that Brd3 and Brd4 were essential for the IL-1β- or TNF-α-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.

Electronic supplementary material

The online version of this article (10.1186/s13018-019-1091-3) contains supplementary material, which is available to authorized users.

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Most cited references 13

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Elongation by RNA polymerase II: the short and long of it.

Danny Reinberg, John. Sims, Rimma Belotserkovskaya (2004)

Appreciable advances into the process of transcript elongation by RNA polymerase II (RNAP II) have identified this stage as a dynamic and highly regulated step of the transcription cycle. Here, we discuss the many factors that regulate the elongation stage of transcription. Our discussion includes the classical elongation factors that modulate the activity of RNAP II, and the more recently identified factors that facilitate elongation on chromatin templates. Additionally, we discuss the factors that associate with RNAP II, but do not modulate its catalytic activity. Elongation is highlighted as a central process that coordinates multiple stages in mRNA biogenesis and maturation.

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The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription.

S Flint, Gary LeRoy, Brenden Rickards (2008)

Posttranslational histone modifications are crucial for the modulation of chromatin structure and regulation of transcription. Bromodomains present in many chromatin-associated proteins recognize acetylated lysines in the unstructured N-terminal regions of histones. Here, we report that the double bromodomain proteins Brd2 and Brd3 associate preferentially in vivo with hyperacetylated chromatin along the entire lengths of transcribed genes. Brd2- and Brd3-associated chromatin is significantly enriched in H4K5, H4K12, and H3K14 acetylation and contains relatively little dimethylated H3K9. Both Brd2 and Brd3 allowed RNA polymerase II to transcribe through nucleosomes in a defined transcription system. Such activity depended on specific histone H4 modifications known to be recognized by the Brd proteins. We also demonstrate that Brd2 has intrinsic histone chaperone activity and is required for transcription of the cyclin D1 gene in vivo. These data identify proteins that render nucleosomes marked by acetylation permissive to the passage of elongating RNA polymerase II.

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Oxygen-sensitive mitochondrial accumulation of cystathionine β-synthase mediated by Lon protease.

Zongbao Zhao, Guangdong Yang, Huajian Teng … (2013)

Oxygen-sensitive accumulation and degradation, two opposite but intrinsically linked events, of heme proteins in mitochondria affect mitochondrial functions, including bioenergetics and oxygen-sensing processes. Cystathionine β-synthase (CBS) contains a prosthetic heme group and catalyzes the production of hydrogen sulfide in mammalian cells. Here we show that CBS proteins were present in liver mitochondria at a low level under normoxia conditions. Ischemia/hypoxia increased the accumulation of CBS proteins in mitochondria. The normalization of oxygen partial pressure accelerated the degradation of CBS proteins. Lon protease, a major degradation enzyme in mitochondrial matrix, recognized and degraded mitochondrial CBS by specifically targeting at the oxygenated heme group of CBS proteins. The accumulation of CBS in mitochondria increased hydrogen sulfide production, which prevented Ca(2+)-mediated cytochrome c release from mitochondria and decreased reactive oxygen species generation. Mitochondrial accumulation of heme oxygenase-1, another heme protein, was also regulated by oxygen level and Lon protease in the same mechanism as for CBS. Our findings provide a fundamental and general mechanism for oxygen-sensitive regulation of mitochondrial functions by linking oxygenation level to the accumulation/degradation of mitochondrial heme proteins.

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Author and article information

Contributors

Jin Dai: daijin_nju@163.com

Sheng Zhou: zhousheng0719@126.com

Qiting Ge: geqt@nicemice.cn

Jinzhong Qin: qinjiz@nicemice.cn

Jianxin Li: lijxnju@nju.edu.cn

Huangxian Ju: hxju@nju.edu.cn

Yi Cao: caoyi@nju.edu.cn

Minghao Zheng: minghao.zheng@uwa.edu.au

Chaojun Li: licj@nju.edu.cn

Xiang Gao: gaoxiang@nju.edu.cn

Huajian Teng: +86(25)82217016 , tenghj@hotmail.com

Qing Jiang:

ORCID: http://orcid.org/0000-0002-2552-9686

+86(25)82217016 , qingj@nju.edu.cn

Journal

Journal ID (nlm-ta): J Orthop Surg Res

Journal ID (iso-abbrev): J Orthop Surg Res

Title: Journal of Orthopaedic Surgery and Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1749-799X

Publication date (Electronic): 20 February 2019

Publication date PMC-release: 20 February 2019

Publication date Collection: 2019

Volume: 14

Electronic Location Identifier: 59

Affiliations

[1 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital, Medical School, , Nanjing University, ; Zhongshan Road 321, Nanjing, 210008 Jiangsu People’s Republic of China

[2 ]GRID grid.452564.4, The Model Animal Research Center of Nanjing University, ; Xuefu Road, Nanjing, 210032 Jiangsu People’s Republic of China

[3 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, State Key Laboratory of Analytical Chemistry for Life Science, , Nanjing University, ; Hankou Road, Nanjing, 210093 People’s Republic of China

[4 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure and Department of Physics, , Nanjing University, ; Hankou Road, Nanjing, 210093 People’s Republic of China

[5 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, Sir Charles Gairdner Hospital, School of Surgery, , The University of Western Australia, ; 35 Stirling Highway, Perth, 6009 Australia

[6 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center and School of Medicine, , Nanjing University, ; Nanjing, 210093 People’s Republic of China

Author information

Qing Jiang http://orcid.org/0000-0002-2552-9686

Article

Publisher ID: 1091

DOI: 10.1186/s13018-019-1091-3

PMC ID: 6381721

PubMed ID: 30786900

SO-VID: 678727e0-d27c-4ddc-8e07-2a7073126218

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 3 July 2018

Date accepted : 5 February 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81125013

Award ID: 81472116

Award Recipient : Qing Jiang

Custom metadata

ScienceOpen disciplines: Surgery

Keywords: matrix-degrading enzymes,brd,transcription,acetylation

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ScienceOpen disciplines: Surgery

Keywords: matrix-degrading enzymes, brd, transcription, acetylation

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

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Higher order chromatin architecture

Most cited references 13

Elongation by RNA polymerase II: the short and long of it.

The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription.

Oxygen-sensitive mitochondrial accumulation of cystathionine β-synthase mediated by Lon protease.

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