MicroRNA-455-3p modulates cartilage development and degeneration through modification of histone H3 acetylation
MicroRNA-455-3p modulates cartilage development and degeneration through modification of histone H3 acetylation
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MicroRNA-455-3p 通过修饰组蛋白 H3 乙酰化来调节软骨发育和退化
DOI：
10.1016/j.bbamcr.2016.09.010
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发表时间：
2016-12-01
影响因子：
5.1
通讯作者：
Liao, Weiming
中科院分区：
文献类型：
--
作者：
Chen, Weishen;Chen, Lingwu;Liao, Weiming
由I类组蛋白去乙酰化酶（HDAC）调控的组蛋白乙酰化在基质特异性基因转录和软骨发育中起着关键作用。虽然我们以前证明microRNA（miR）-455-3p在软骨形成过程中上调，并能增强早期软骨形成，但这一过程的机制在很大程度上仍不清楚。在这项研究中，我们表征了miR-455- 3 p对组蛋白H3乙酰化的影响及其在软骨发育和变性过程中的作用。我们观察到miR-455- 3 p在增殖和肥大前软骨细胞中高度表达，而HDAC 2和HDAC 8主要在肥大软骨细胞中表达。同时，miR-455- 3 p抑制含有HDAC 2/8的3 '-非翻译区的报告构建体的活性，抑制HDAC 2/8表达，并促进人SW 1353软骨细胞样细胞中胶原2（COL 2A 1）启动子处的组蛋白H3乙酰化。用HDAC抑制剂阿司他丁A（TSA）治疗导致软骨特异性基因的表达增加，并促进糖胺聚糖沉积。此外，TSA抑制基质金属蛋白酶13（Mmp 13）的表达，并促进SOX 9的核转位在白细胞介素-1处理的原代小鼠软骨细胞。最后，HDAC 2/3/8的敲低增加了SRY（性别决定区Y）-box 9（SOX 9），并降低了Runt相关转录因子2（RUNX 2）的表达。综上所述，这些发现表明miR-455- 3 p通过直接靶向HDAC 2/8和促进组蛋白H3乙酰化在软骨形成过程中发挥关键作用，这增加了使用miR-455- 3 p影响软骨形成和软骨退变的可能性。(C)2016爱思唯尔B. V.保留所有权利。
Histone acetylation regulated by class I histone deacetylases (HDACs) plays a pivotal role in matrix-specific gene transcription and cartilage development. While we previously demonstrated that microRNA (miR)-455-3p is upregulated during chondrogenesis and can enhance early chondrogenesis, the mechanism underlying this process remains largely unclear. In this study, we characterized the effect of miR-455-3p on histone H3 acetylation and its role during cartilage development and degeneration. We observed that miR-455-3p was highly expressed in proliferating and pre-hypertrophic chondrocytes, while HDAC2 and HDAC8 were primarily expressed in hypertrophic chondrocytes. Meanwhile, miR-455-3p suppressed the activity of reporter constructs containing the 3'-untranslated regions of HDAC2/8, inhibited HDAC2/8 expression and promoted histone H3 acetylation at the collagen 2 (COL2A1) promoter in human SW1353 chondrocyte-like cells. Treatment with the HDAC inhibitor trichostatin A (TSA) resulted in increased expression of cartilage-specific genes and promoted glycosaminoglycan deposition. Moreover, TSA inhibited matrix metalloproteinase 13 (Mmp13) expression and promoted nuclear translocation of SOX9 in interleukin-l-treated primary mouse chondrocytes. Lastly, knockdown of HDAC2/3/8 increased SRY (sex-determining region Y)-box 9 (SOX9) and decreased Runt-related transcription factor 2 (RUNX2) expression. Taken together, these findings suggest that miR-455-3p plays a critical role during chondrogenesis by directly targeting HDAC2/8 and promoting histone H3 acetylation, which raises possibilities of using miR-455-3p to influence chondrogenesis and cartilage degeneration. (C) 2016 Elsevier B.V. All rights reserved.