State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
PLoS Biol. 2018 Nov 13;16(11):e2006522. doi: 10.1371/journal.pbio.2006522. eCollection 2018 Nov.
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.
在衰老过程中，骨髓间充质干细胞（BMSCs）表现出成骨能力下降，同时伴随着脂肪生成过度，这将导致骨质疏松症。在这里，我们报告组蛋白甲基转移酶 SET 结构域包含蛋白 2（SETD2）催化的 H3 赖氨酸 36 三甲基化（H3K36me3）调节 BMSCs 的谱系分化。通过 Prx1 启动子驱动的条件性 Cre 表达，在小鼠骨髓间充质干细胞（mBMSCs）中删除 Setd2 会导致骨丢失和骨髓脂肪增多。BMSCs 中 Setd2 的缺失促进了向脂肪细胞而不是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 SETD2 的一个功能性靶基因 Lbp，H3K36me3 在此处富集，其表达受 Setd2 缺失的影响。此外，Lbp 的过表达可以部分挽救由于 BMSCs 中 Setd2 缺失导致的成骨不足和脂肪生成增强。进一步的机制研究表明，H3K36 的三甲基化水平可以调节 Lbp 的转录起始和延伸。这些发现表明，SETD2 介导的 H3K36me3 可以调节体外和体内间充质干细胞（MSCs）的细胞命运，表明通过靶向 SETD2 调节 H3K36me3 水平和/或施用下游 LBP 可能代表代谢性骨病（如骨质疏松症）新治疗的潜在治疗方法。
