Recruitment of Brd3 and Brd4 to acetylated chromatin is essential for proinflammatory cytokine-induced matrix-degrading enzyme expression
| Autor: | Huangxian Ju, Huajian Teng, Chao-Jun Li, Xiang Gao, Sheng Zhou, Jin Dai, Jinzhong Qin, Minghao Zheng, Qiting Ge, Qing Jiang, Jianxin Li, Yi Cao |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Matrix-degrading enzymes
lcsh:Diseases of the musculoskeletal system Cell Cycle Proteins RNA polymerase II Gene Expression Regulation Enzymologic Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine lcsh:Orthopedic surgery Cell Line Tumor Gene expression Transcriptional regulation Humans Medicine Orthopedics and Sports Medicine Transcription factor 030203 arthritis & rheumatology Enzyme Gene 030222 orthopedics Gene knockdown biology business.industry Nuclear Proteins RNA-Binding Proteins Acetylation Chromatin Cell biology Brd lcsh:RD701-811 biology.protein Cytokines Surgery Inflammation Mediators lcsh:RC925-935 business Transcription Transcription Factors Research Article |
| Zdroj: | Journal of Orthopaedic Surgery and Research, Vol 14, Iss 1, Pp 1-10 (2019) Journal of Orthopaedic Surgery and Research |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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