H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells.
H3K36 trimethylation mediated by SETD2 regulates the fate of bone marrow mesenchymal stem cells.
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SETD2介导的H3K36三甲基化调节骨髓间充质干细胞的命运
DOI：
10.1371/journal.pbio.2006522
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发表时间：
2018-11
期刊：
影响因子：
9.8
通讯作者：
Zou W
中科院分区：
文献类型：
--
作者：
Wang L;Niu N;Li L;Shao R;Ouyang H;Zou W
在衰老过程中，骨髓间充质干细胞（BMSCs）表现为成骨能力下降，并伴有脂肪生成过剩，从而导致骨质疏松症。在这里，我们报道了H3赖氨酸36三甲基化（H3K36me3），由组蛋白甲基转移酶SET-domain-containing 2 （SETD2）催化，调节骨髓间充质干细胞的谱系承诺。小鼠骨髓间充质干细胞（mBMSCs）中Setd2的缺失，通过Prx1启动子驱动的条件Cre表达，导致骨质流失和骨髓肥胖。体外培养的骨髓间充质干细胞中Setd2的缺失促进了向脂肪细胞而非成骨细胞的分化倾向。通过RNA测序（RNA-seq）和染色质免疫沉淀测序（ChIP-seq）数据的联合分析，我们确定了一个SETD2功能靶基因Lbp， H3K36me3在该基因上富集，其表达受SETD2缺乏的影响。此外，脂多糖结合蛋白（lipopolaccharide -binding protein， LBP）的过表达可以部分修复骨髓间充质干细胞中Setd2缺失导致的成骨缺失和脂肪生成增强。进一步的机制研究表明，H3K36的三甲基化水平可以调节Lbp转录的起始和延伸。这些研究结果表明，SETD2介导的H3K36me3可以在体外和体内调节间充质干细胞（mesenchymal stem cells, MSCs）的细胞命运，表明通过靶向SETD2和/或给药下游LBP调控H3K36me3水平可能为代谢性骨病（如骨质疏松症）的新治疗方法提供了潜在的治疗途径。
During the aging process, bone marrow mesenchymal stem cells (BMSCs) exhibit declined osteogenesis accompanied by excess adipogenesis, which will lead to osteoporosis. Here, we report that the H3 lysine 36 trimethylation (H3K36me3), catalyzed by histone methyltransferase SET-domain-containing 2 (SETD2), regulates lineage commitment of BMSCs. Deletion of Setd2 in mouse bone marrow mesenchymal stem cells (mBMSCs), through conditional Cre expression driven by Prx1 promoter, resulted in bone loss and marrow adiposity. Loss of Setd2 in BMSCs in vitro facilitated differentiation propensity to adipocytes rather than to osteoblasts. Through conjoint analysis of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data, we identified a SETD2 functional target gene, Lbp, on which H3K36me3 was enriched, and its expression was affected by Setd2 deficiency. Furthermore, overexpression of lipopolysaccharide-binding protein (LBP) could partially rescue the lack of osteogenesis and enhanced adipogenesis resulting from the absence of Setd2 in BMSCs. Further mechanistic studies demonstrated that the trimethylation level of H3K36 could regulate Lbp transcriptional initiation and elongation. These findings suggest that H3K36me3 mediated by SETD2 could regulate the cell fate of mesenchymal stem cells (MSCs) in vitro and in vivo, indicating that the regulation of H3K36me3 level by targeting SETD2 and/or the administration of downstream LBP may represent a potential therapeutic way for new treatment in metabolic bone diseases, such as osteoporosis.
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