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

Ruili Yang, Tingting Yu, Xiaoxing Kou, Xiang Gao, Chider Chen, Dawei Liu, Yanheng Zhou () and Songtao Shi ()
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Ruili Yang: Peking University School & Hospital of Stomatology
Tingting Yu: Peking University School & Hospital of Stomatology
Xiaoxing Kou: Peking University School & Hospital of Stomatology
Xiang Gao: School of Dental Medicine
Chider Chen: School of Dental Medicine
Dawei Liu: Peking University School & Hospital of Stomatology
Yanheng Zhou: Peking University School & Hospital of Stomatology
Songtao Shi: School of Dental Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04464-6

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