Tet2 Regulates Osteoclast Differentiation by Interacting with Runx1 and Maintaining Genomic 5-Hydroxymethylcytosine (5hmC)

Yajing Chu, Zhigang Zhao, David Wayne Sant, Ganqian Zhu, Sarah M. Greenblatt, Lin Liu, Jinhuan Wang, Zeng Cao, Jeanette Cheng Tho, Shi Chen, Xiaochen Liu, Peng Zhang, Jaroslaw P. Maciejewski, Stephen Nimer, Gaofeng Wang, Weiping Yuan, Feng Chun Yang, Mingjiang Xu

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

As a dioxygenase, Ten-Eleven Translocation 2 (TET2) catalyzes subsequent steps of 5-methylcytosine (5mC) oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hematopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Deletion of Tet2 impairs the differentiation of osteoclast precursor cells (macrophages) and their maturation into bone-resorbing osteoclasts in vitro. Furthermore, Tet2−/− mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cebpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine (5hmC) and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runx1 and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runx1 and the maintenance of genomic 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and treatment of abnormal bone mass caused by the deregulation of osteoclast activities.

Original languageEnglish (US)
Pages (from-to)172-186
Number of pages15
JournalGenomics, Proteomics and Bioinformatics
Volume16
Issue number3
DOIs
StatePublished - Jun 2018

Keywords

  • 5hmC
  • Macrophage
  • Osteoclast
  • Runx1
  • Tet2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Computational Mathematics

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  • Cite this

    Chu, Y., Zhao, Z., Sant, D. W., Zhu, G., Greenblatt, S. M., Liu, L., Wang, J., Cao, Z., Tho, J. C., Chen, S., Liu, X., Zhang, P., Maciejewski, J. P., Nimer, S., Wang, G., Yuan, W., Yang, F. C., & Xu, M. (2018). Tet2 Regulates Osteoclast Differentiation by Interacting with Runx1 and Maintaining Genomic 5-Hydroxymethylcytosine (5hmC). Genomics, Proteomics and Bioinformatics, 16(3), 172-186. https://doi.org/10.1016/j.gpb.2018.04.005