长链非编码 RNA ODIR1 通过 FBXO25/H2BK120ub/H3K4me3/OSX 轴抑制人脐带来源间充质干细胞的成骨分化。

LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis.

机构信息

NHC Key Laboratory of Carcinogenesis, Hunan Provincial Tumor Hospital, Central South University, Changsha, 410013, China.

The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, China.

出版信息

Cell Death Dis. 2019 Dec 11;10(12):947. doi: 10.1038/s41419-019-2148-2.

Long noncoding RNAs (lncRNAs) have been demonstrated to be important regulators during the osteogenic differentiation of mesenchymal stem cells (MSCs). We analyzed the lncRNA expression profile during osteogenic differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and identified a significantly downregulated lncRNA RP11-527N22.2, named osteogenic differentiation inhibitory lncRNA 1, ODIR1. In hUC-MSCs, ODIR1 knockdown significantly promoted osteogenic differentiation, whereas overexpression inhibited osteogenic differentiation in vitro and in vivo. Mechanistically, ODIR1 interacts with F-box protein 25 (FBXO25) and facilitates the proteasome-dependent degradation of FBXO25 by recruiting Cullin 3 (CUL3). FBXO25 increases the mono-ubiquitination of H2BK120 (H2BK120ub) which subsequently promotes the trimethylation of H3K4 (H3K4me3). Both H2BK120ub and H3K4me3 form a loose chromatin structure, inducing the transcription of the key transcription factor osterix (OSX) and increasing the expression of the downstream osteoblast markers, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP). In summary, ODIR1 acts as a key negative regulator during the osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis, which may provide a novel understanding of lncRNAs that regulate the osteogenesis of MSCs and a potential therapeutic strategy for the regeneration of bone defects.

长链非编码 RNA（lncRNA）已被证明在间充质干细胞（MSCs）的成骨分化过程中是重要的调节因子。我们分析了人脐带间充质干细胞（hUC-MSCs）成骨分化过程中的 lncRNA 表达谱，鉴定出一个显著下调的 lncRNA RP11-527N22.2，命名为成骨分化抑制 lncRNA 1（ODIR1）。在 hUC-MSCs 中，ODIR1 敲低显著促进成骨分化，而过表达则在体外和体内抑制成骨分化。机制上，ODIR1 与 F-box 蛋白 25（FBXO25）相互作用，并通过募集 Cullin 3（CUL3）促进 FBXO25 的蛋白酶体依赖性降解。FBXO25 增加 H2BK120 的单泛素化（H2BK120ub），随后促进 H3K4 的三甲基化（H3K4me3）。H2BK120ub 和 H3K4me3 形成一种松散的染色质结构，诱导关键转录因子骨形成蛋白 2（OSX）的转录，并增加下游成骨标志物骨钙素（OCN）、骨桥蛋白（OPN）和碱性磷酸酶（ALP）的表达。总之，ODIR1 通过 FBXO25/H2BK120ub/H3K4me3/OSX 轴在 hUC-MSCs 的成骨分化中起关键负调控作用，这可能为调控 MSC 成骨的 lncRNA 提供新的认识，并为骨缺损的再生提供潜在的治疗策略。