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

Author

Listed:
  • 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
    Zhejiang University)

  • 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
    Zhejiang University)

  • Weiguo Zou

    (Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
    University of Chinese Academy of Sciences)

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.

Suggested Citation

  • Lijun Wang & Xiuling You & Dengfeng Ruan & Rui Shao & Hai-Qiang Dai & Weiliang Shen & Guo-Liang Xu & Wanlu Liu & Weiguo Zou, 2022. "TET enzymes regulate skeletal development through increasing chromatin accessibility of RUNX2 target genes," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32138-x
    DOI: 10.1038/s41467-022-32138-x
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    References listed on IDEAS

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    1. Qiang Chen & Yibin Chen & Chunjing Bian & Ryoji Fujiki & Xiaochun Yu, 2013. "TET2 promotes histone O-GlcNAcylation during gene transcription," Nature, Nature, vol. 493(7433), pages 561-564, January.
    2. Hai-Qiang Dai & Bang-An Wang & Lu Yang & Jia-Jia Chen & Guo-Chun Zhu & Mei-Ling Sun & Hao Ge & Rui Wang & Deborah L. Chapman & Fuchou Tang & Xin Sun & Guo-Liang Xu, 2016. "TET-mediated DNA demethylation controls gastrulation by regulating Lefty–Nodal signalling," Nature, Nature, vol. 538(7626), pages 528-532, October.
    3. Toru Fukuda & Shu Takeda & Ren Xu & Hiroki Ochi & Satoko Sunamura & Tsuyoshi Sato & Shinsuke Shibata & Yutaka Yoshida & Zirong Gu & Ayako Kimura & Chengshan Ma & Cheng Xu & Waka Bando & Koji Fujita & , 2013. "Sema3A regulates bone-mass accrual through sensory innervations," Nature, Nature, vol. 497(7450), pages 490-493, May.
    4. Hao Chen & Bo Hu & Xiao Lv & Shouan Zhu & Gehua Zhen & Mei Wan & Amit Jain & Bo Gao & Yu Chai & Mi Yang & Xiao Wang & Ruoxian Deng & Lei Wang & Yong Cao & Shuangfei Ni & Shen Liu & Wen Yuan & Huajiang, 2019. "Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    5. Kristine Williams & Jesper Christensen & Marianne Terndrup Pedersen & Jens V. Johansen & Paul A. C. Cloos & Juri Rappsilber & Kristian Helin, 2011. "TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity," Nature, Nature, vol. 473(7347), pages 343-348, May.
    6. Shawon Debnath & Alisha R. Yallowitz & Jason McCormick & Sarfaraz Lalani & Tuo Zhang & Ren Xu & Na Li & Yifang Liu & Yeon Suk Yang & Mark Eiseman & Jae-Hyuck Shim & Meera Hameed & John H. Healey & Mat, 2018. "Discovery of a periosteal stem cell mediating intramembranous bone formation," Nature, Nature, vol. 562(7725), pages 133-139, October.
    7. Yoshiki Omatsu & Shota Aiba & Tomonori Maeta & Kei Higaki & Kazunari Aoki & Hitomi Watanabe & Gen Kondoh & Riko Nishimura & Shu Takeda & Ung-il Chung & Takashi Nagasawa, 2022. "Runx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    8. Zhen Liu & Xiao Yao & Guang Yan & YiChi Xu & Jun Yan & Weiguo Zou & Gang Wang, 2016. "Mediator MED23 cooperates with RUNX2 to drive osteoblast differentiation and bone development," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    9. Shawn J. Cokus & Suhua Feng & Xiaoyu Zhang & Zugen Chen & Barry Merriman & Christian D. Haudenschild & Sriharsa Pradhan & Stanley F. Nelson & Matteo Pellegrini & Steven E. Jacobsen, 2008. "Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning," Nature, Nature, vol. 452(7184), pages 215-219, March.
    10. Kyriel M. Pineault & Jane Y. Song & Kenneth M. Kozloff & Daniel Lucas & Deneen M. Wellik, 2019. "Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
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