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

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

Author: Yajing CHU ¹ ; Zhigang ZHAO ² ; David Wayne SANT ³ ; Ganqian ZHU ⁴ ; Sarah M GREENBLATT ⁵ ; Lin LIU ⁶ ; Jinhuan WANG ⁷ ; Zeng CAO ⁶ ; Jeanette Cheng THO ⁴ ; Shi CHEN ⁴ ; Xiaochen LIU ⁴ ; Peng ZHANG ⁴ ; Jaroslaw P MACIEJEWSKI ⁸ ; Stephen NIMER ⁵ ; Gaofeng WANG ³ ; Weiping YUAN ¹ ; Feng-Chun YANG ⁹ ; Mingjiang XU ¹⁰
Author Information

1. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
2. Department of Hematology and Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: zzhao01@tmu.edu.cn.
3. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
4. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
5. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
6. Department of Hematology and Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
7. Department of Oncology, The Second Affiliated Hospital of Tianjin Medical University, Tianjin 300211, China.
8. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
9. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: fxy37@med.miami.edu.
10. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: mxx51@miami.edu.
Publication Type:Journal Article
Keywords: 5hmC; Macrophage; Osteoclast; Runx1; Tet2
MeSH: 5-Methylcytosine; analogs & derivatives; chemistry; metabolism; Animals; Cell Differentiation; Cells, Cultured; Core Binding Factor Alpha 2 Subunit; genetics; metabolism; DNA-Binding Proteins; physiology; Genome; Genomics; Mice; Mice, Knockout; Osteoclasts; cytology; metabolism; Proto-Oncogene Proteins; physiology
From: Genomics, Proteomics & Bioinformatics 2018;16(3):172-186
CountryChina
Language:English
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.