LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK12Oub/H3K4me3/OSX axis
LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK12Oub/H3K4me3/OSX axis
复制标题
LncRNA ODIR1 通过 FBXO25/H2BK12Oub/H3K4me3/OSX 轴抑制 hUC-MSC 的成骨分化
DOI：
10.1038/s41419-019-2148-2
复制
发表时间：
2019-12-11
影响因子：
9
通讯作者：
Shuai, Cijun
中科院分区：
文献类型：
--
作者：
He, Shiwei;Yang, Sheng;Shuai, Cijun
长非编码RNA(LncRNAs)是间充质干细胞(MSCs)成骨分化的重要调控因子。我们分析了人脐血间充质干细胞(Huc-MSCs)成骨分化过程中LncRNA的表达谱，发现了一个显著下调的LncRNA RP11-527N22.2，命名为成骨分化抑制LncRNA 1，ODIR1。在Huc-MSCs中，ODIR1基因敲除显著促进成骨分化，而在体外和体内过表达则抑制成骨分化。在机制上，ODIR1与F-box蛋白25(FBXO25)相互作用，并通过招募cullin 3(CUL3)促进蛋白酶体依赖的FBXO25的降解。FBXO25增加了H2BK120(H2BK12Oub)的单泛素化，从而促进了H3K4(H3K4me3)的三甲基化。H2BK12Oub和H3K4me3都形成疏松的染色质结构，诱导关键转录因子OSX的转录，并增加下游成骨细胞标志物骨钙素(OCN)、骨桥蛋白(OPN)和碱性磷酸酶(ALP)的表达。综上所述，ODIR1在Huc-MSCs通过FBXO25/H2BK12Oub/H3K4me3/OSX轴向成骨分化的过程中发挥着关键的负调控作用，这可能为我们提供对调控MSCs成骨的lncRNAs的新认识，并为骨缺损的再生提供潜在的治疗策略。
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 monoubiquitination of H2BK120 (H2BK12Oub) which subsequently promotes the trimethylation of H3K4 (H3K4me3). Both H2BK12Oub 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/H2BK12Oub/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.