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Nature communications v.9 no.1, 2018년, pp.2143 - 2143   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter

Yang, Ruili    (Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China   ); Yu, Tingting    (Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA   ); Kou, Xiaoxing    (Sino-US joint Research Center of Oral Tissue-derived Stem Cells, PKU Industrial Park, Building 10 First Floor, Beiqing Road, Changping District, Beijing, 102200, China   ); Gao, Xiang    (Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China   ); Chen, Chider    (Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA   ); Liu, Dawei    (Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing, 100081, China   ); Zhou, Yanheng    (Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA, 19104, USA   ); Shi, Songtao    (Department of Anatomy and Cell Biology, Univ  );
  • 초록  

    Ten-eleven translocation (Tet) family-mediated DNA oxidation represents an epigenetic modification capable of converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which regulates various biological processes. However, it is unknown whether Tet family affects mesenchymal stem cells (MSCs) or the skeletal system. Here we show that depletion of Tet1 and Tet2 results in impaired self-renewal and differentiation of bone marrow MSCs (BMMSCs) and a significant osteopenia phenotype. Tet1 and Tet2 deficiency reduces demethylation of the P2rX7 promoter and downregulates exosome release, leading to intracellular accumulation of miR-297a-5p, miR-297b-5p, and miR-297c-5p. These miRNAs inhibit Runx2 signaling to impair BMMSC function. We show that overexpression of P2rX7 rescues the impaired BMMSCs and osteoporotic phenotype in Tet1 and Tet2 double knockout mice. These results indicate that Tet1 and Tet2 play a critical role in maintaining BMMSC and bone homeostasis through demethylation of P2rX7 to control exosome and miRNA release. This Tet/P2rX7/Runx2 cascade may serve as a target for the development of novel therapies for osteopenia disorders.


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