期刊
GENOMICS PROTEOMICS & BIOINFORMATICS
卷 16, 期 3, 页码 172-186出版社
ELSEVIER
DOI: 10.1016/j.gpb.2018.04.005
关键词
Tet2; 5hmC; Macrophage; Osteoclast; Runx1
资金
- National Institutes of Health [CA172408, HL112294]
- Leukemia AMP
- Lymphoma Society (LLS) (SCOR program)
- University of Miami Sylvester Comprehensive Cancer Center (SCCC), the United States
- Ministry of Science and Technology of China [2017YFA0103402]
- National Natural Science Foundation of China [81629001, 81670102, 81600136, 81421002]
- CAMS Innovation Fund for Medical Sciences [2017-I2M-3-015, 2016-I2M-1-017]
- Tianjin Application Foundation and Advanced Technology Research Program [16JCYBJC25200, 17JCQNJC09800]
- SKLEH-Pilot Research Grand [ZK16-3]
- Peking Union Medical College Youth Fund, China [3332016092]
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(-1-) 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 Runxl 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 Runxl 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.
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