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TET enzymes regulate skeletal development through increasing chromatin accessibility of RUNX2 target genes
Nature Communications ( IF 16.6 ) Pub Date : 2022-08-11 , DOI: 10.1038/s41467-022-32138-x
Lijun Wang 1 , Xiuling You 2 , Dengfeng Ruan 3, 4 , Rui Shao 1 , Hai-Qiang Dai 2 , Weiliang Shen 3 , Guo-Liang Xu 2 , Wanlu Liu 3, 4 , Weiguo Zou 1, 2
Affiliation  

The Ten-eleven translocation (TET) family of dioxygenases mediate cytosine demethylation by catalyzing the oxidation of 5-methylcytosine (5mC). TET-mediated DNA demethylation controls the proper differentiation of embryonic stem cells and TET members display functional redundancy during early gastrulation. However, it is unclear if TET proteins have functional significance in mammalian skeletal development. Here, we report that Tet genes deficiency in mesoderm mesenchymal stem cells results in severe defects of bone development. The existence of any single Tet gene allele can support early bone formation, suggesting a functional redundancy of TET proteins. Integrative analyses of RNA-seq, Whole Genome Bisulfite Sequencing (WGBS), 5hmC-Seal and Assay for Transposase-Accessible Chromatin (ATAC-seq) demonstrate that TET-mediated demethylation increases the chromatin accessibility of target genes by RUNX2 and facilities RUNX2-regulated transcription. In addition, TET proteins interact with RUNX2 through their catalytic domain to regulate cytosine methylation around RUNX2 binding region. The catalytic domain is indispensable for TET enzymes to regulate RUNX2 transcription activity on its target genes and to regulate bone development. These results demonstrate that TET enzymes function to regulate RUNX2 activity and maintain skeletal homeostasis.



中文翻译:

TET 酶通过增加 RUNX2 靶基因的染色质可及性来调节骨骼发育

双加氧酶的十一十一易位 (TET) 家族通过催化 5-甲基胞嘧啶 (5mC) 的氧化来介导胞嘧啶去甲基化。TET 介导的 DNA 去甲基化控制胚胎干细胞的适当分化,TET 成员在早期原肠胚形成过程中表现出功能冗余。然而,尚不清楚 TET 蛋白是否在哺乳动物骨骼发育中具有功能意义。在这里,我们报告中胚层间充质干细胞中的Tet基因缺陷导致骨骼发育的严重缺陷。任何单个Tet的存在基因等位基因可以支持早期骨形成,表明 TET 蛋白的功能冗余。RNA-seq、全基因组亚硫酸氢盐测序 (WGBS)、5hmC-Seal 和转座酶可及染色质分析 (ATAC-seq) 的综合分析表明,TET 介导的去甲基化增加了 RUNX2 和设施 RUNX2 调节的靶基因的染色质可及性转录。此外,TET 蛋白通过其催化结构域与 RUNX2 相互作用,以调节 RUNX2 结合区域周围的胞嘧啶甲基化。催化结构域对于 TET 酶调节其靶基因上的 RUNX2 转录活性和调节骨骼发育是必不可少的。这些结果表明,TET 酶具有调节 RUNX2 活性和维持骨骼稳态的功能。

更新日期:2022-08-11
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