1.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
Genomics, Proteomics & Bioinformatics 2018;16(3):172-186
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.
5-Methylcytosine
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analogs & derivatives
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chemistry
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metabolism
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Animals
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Cell Differentiation
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Cells, Cultured
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Core Binding Factor Alpha 2 Subunit
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genetics
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metabolism
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DNA-Binding Proteins
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physiology
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Genome
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Genomics
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Mice
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Mice, Knockout
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Osteoclasts
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cytology
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metabolism
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Proto-Oncogene Proteins
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physiology