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Journal of Orthopaedic Surgery and Research

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Open Access 01-12-2019 | Cytokines | Research article

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

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

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2019

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.

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Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33–42.PubMedCrossRef

Bondeson J, Wainwright S, Hughes C, Caterson B. The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clin Exp Rheumatol. 2008;26(1):139–45.PubMed

Vincenti MP, Brinckerhoff CE. Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res. 2002;4(3):157–64.PubMedCrossRef

Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067–73.PubMedPubMedCentralCrossRef

Dai J, Zhou S, Ge Q, Qin J, Chen D, Xu Z, et al. Bi-directional regulation of cartilage metabolism by inhibiting BET proteins-analysis of the effect of I-BET151 on human chondrocytes and murine joints. J Orthop Surg Res. 2018;13(1):118.PubMedPubMedCentralCrossRef

Belkinal AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer. 2012;12(7):465–77.CrossRef

Wu SY, Chiang CM. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J Biol Chem. 2007;282(18):13141–5.PubMedCrossRef

Nie M, Pang L, Inoue H, Knox AJ. Transcriptional regulation of cyclooxygenase 2 by bradykinin and interleukin-1beta in human airway smooth muscle cells: involvement of different promoter elements, transcription factors, and histone h4 acetylation. Mol Cell Biol. 2003;23(24):9233–44.PubMedPubMedCentralCrossRef

Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol. 2000;20(18):6891–903.PubMedPubMedCentralCrossRef

10.

Chen YJ, Chang LS. NFκB- and AP-1-mediated DNA looping regulates matrix metalloproteinase-9 transcription in TNF-α-treated human leukemia U937 cells. Biochim Biophys Acta. 2015;1849(10):1248–59.PubMedCrossRef

11.

Gebauer M, Saas J, Sohler F, Haag J, Söder S, Pieper M, et al. Comparison of the chondrosarcoma cell line SW1353 with primary human adult articular chondrocytes with regard to their gene expression profile and reactivity to IL-1β. Osteoarthr Cartil. 2005;13:697–708.CrossRef

12.

Tew SR, Murdoch AD, Rauchenberg RP, Hardingham TE. Cellular metnods in cartilage research: primary human chondrocytes in culture and chondrogenesis in human bone marrow stem cells. Methods. 2008;45:2–9.PubMedCrossRef

13.

Teng H, Wu B, Zhao K, Yang G, Wu L, Wang R. Oxygen-senesitive mitochondrial accumulation of cystathionine β-synthase meidiated by Lon protease. Proc Natl Acad Sci U S A. 2013;110:12679–84.PubMedPubMedCentralCrossRef

14.

Yang Z, Yik JH, Chen R, He N, Jang MK, Ozato K, et al. Recruitment of p-TEFb for stimulation of transcriptional elongation by the bromodomanin protein Brd4. Mol Cell. 2005;19:535–45.PubMedCrossRef

15.

Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain protein Brd4 is a positive regulatory component of p-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005;19:523–34.PubMedCrossRef

16.

Sims RJ 3rd, Belotserkovskaya R, Reinberg D. Elongation by RNA polymerase II: the short and long of it. Genes Dev. 2004;18:2437–68.PubMedCrossRef

17.

Hargreaves DC, Horng T, Medzhitov R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell. 2009;138:129–45.PubMedPubMedCentralCrossRef

18.

Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci U S A. 2003;100:8758–63.PubMedPubMedCentralCrossRef

19.

LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell. 2008;30:51–60.PubMedPubMedCentralCrossRef

20.

Chen WL, Sheu JR, Hsiao CJ, Hsiao SH, Chung CL, Hsiao G. Histone deacetylase inhibitor impairs plasminogen activator inhibitor-1 expression via inhibiting TNF-α-activated MAPK/AP-1 signaling cascade. Biomed Res Int. 2014;2014:231012.PubMedPubMedCentral

21.

Wang Y, Wang Y, Luo M, Wu H, Kong L, Xin Y, et al. Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation. Biochim Biophys Acta. 2015;1852(1):34–46.PubMedCrossRef

22.

Young DA, Lakey RL, Pennington CJ, Jones D, Kevorkian L, Edwards DR, et al. Histone deacetylase inhibitors modulate metalloproteinase gene expression in chondrocytes and block cartilage resorption. Arthritis Res Ther. 2005:R503–12.

23.

Culley KL, Hui W, Barter MJ, Davidson RK, Swingler TE, Destrument AP, et al. Class I histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation. Arthritis Rheumatol. 2013;65:1822–30.CrossRef

24.

Angiolilli C, Kabala PA, Grabiec AM, Van Baarsen IM, Ferguson BS, García S, et al. Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. Ann Rheum Dis. 2017;76(1):277–85.PubMedCrossRef

25.

Ziesché E, Kettner-Buhrow D, Weber A, Wittwer T, Jurida L, Soelch J, et al. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB. Nucleic Acids Res. 2013;41(1):90–109.PubMedCrossRef

Title: Recruitment of Brd3 and Brd4 to acetylated chromatin is essential for proinflammatory cytokine-induced matrix-degrading enzyme expression
Authors: Jin Dai
Sheng Zhou
Qiting Ge
Jinzhong Qin
Jianxin Li
Huangxian Ju
Yi Cao
Minghao Zheng
Chaojun Li
Xiang Gao
Huajian Teng
Qing Jiang
Publication date: 01-12-2019
Publisher: BioMed Central
Keyword: Cytokines
Published in: Journal of Orthopaedic Surgery and Research / Issue 1/2019
Electronic ISSN: 1749-799X
DOI: https://doi.org/10.1186/s13018-019-1091-3

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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