title: MBD3L2 promotes Tet2 enzymatic activity for mediating 5-methylcytosine oxidation.
abstract: Ten-eleven translocation (Tet) proteins are key players involved in the dynamic regulation of cytosine methylation and demethylation. Inactivating mutations of Tet2 are frequently found in human malignancies, highlighting the essential role of Tet2 in cellular transformation. However, the factors that control Tet enzymatic activity remain largely unknown. Here, we found that methyl-CpG-binding domain protein 3 (MBD3) and its homolog MBD3-like 2 (MBD3L2) can specifically modulate the enzymatic activity of Tet2 protein, but not Tet1 and Tet3 proteins, in converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Moreover, MBD3L2 is more effective than MBD3 in promoting Tet2 enzymatic activity through strengthening the binding affinity between Tet2 and the methylated DNA target. Further analysis revealed pronounced decreases in 5mC levels at MBD3L2 and Tet2 co-occupied genomic regions, most of which are promoter elements associated with either cancer-related genes or genes involved in the regulation of cellular metabolic processes. Our data add new insights into the regulation of Tet2 activity by MBD3 and MBD3L2, and into how that affects Tet2-mediated modulation of its target genes in cancer development. Thus, they have important applications in understanding how dysregulation of Tet2 might contribute to human malignancy.
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, 130 Dong-An Road, Shanghai 200032, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Peng
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, 130 Dong-An Road, Shanghai 200032, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Epigenetics, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Ruitu
authors.initials: R
authors.lastname: Lv
authors.affiliation: Biomedical Core Facility, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Zou
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
authors.forename: Shihua
authors.initials: S
authors.lastname: Dong
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
authors.forename: Huaibing
authors.initials: H
authors.lastname: Luo
authors.affiliation: Laboratory of Epigenetics, School of Basic Medicine and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China wufz@fudan.edu.cn wenqiangyu@fudan.edu.cn.
authors.forename: Feizhen
authors.initials: F
authors.lastname: Wu
authors.affiliation: Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, 130 Dong-An Road, Shanghai 200032, China State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200032, China wufz@fudan.edu.cn wenqiangyu@fudan.edu.cn.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Yu
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D057809:HEK293 Cells; D006801:Humans; D010084:Oxidation-Reduction; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C115369:MBD3 protein, human; C474632:MBD3L2 protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D044503:5-Methylcytosine; D049308:Dioxygenases; C541081:TET2 protein, human
keywords: DNA demethylation; Enzymatic activity; Epigenetics; MBD3; MBD3L2; Tet2