title: Regulation of TET protein stability by calpains.
abstract: DNA methylation at the fifth position of cytosine (5mC) is an important epigenetic modification that affects chromatin structure and gene expression. Recent studies have established a critical function of the Ten-eleven translocation (Tet) family of proteins in regulating DNA methylation dynamics. Three Tet genes have been identified in mammals, and they all encode for proteins capable of oxidizing 5mC as part of the DNA demethylation process. Although regulation of Tet expression at the transcriptional level is well documented, how TET proteins are regulated at posttranslational level is poorly understood. In this study, we report that all three TET proteins are direct substrates of calpains, a family of calcium-dependent proteases. Specifically, calpain1 mediates TET1 and TET2 turnover in mouse ESCs, and calpain2 regulates TET3 level during differentiation. This study provides evidence that TET proteins are subject to calpain-mediated degradation.
authors.affiliation: Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: yzhang@genetics.med.harvard.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D055550:Protein Stability; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C540839:TET1 protein, mouse; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse; D002154:Calpain