TET enzymes regulate skeletal development through increasing chromatin accessibility of RUNX2 target genes

Lijun Wang, Xiuling You, Dengfeng Ruan, Rui Shao, Hai-Qiang Dai, Weiliang Shen, Guo-Liang Xu, Wanlu Liu () and Weiguo Zou ()
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Lijun Wang: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Xiuling You: University of Chinese Academy of Sciences
Dengfeng Ruan: Zhejiang University School of Medicine
Rui Shao: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Hai-Qiang Dai: University of Chinese Academy of Sciences
Weiliang Shen: Zhejiang University School of Medicine
Guo-Liang Xu: University of Chinese Academy of Sciences
Wanlu Liu: Zhejiang University School of Medicine
Weiguo Zou: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32138-x

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