Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX

被引:292
作者
Ko, Myunggon [1 ]
An, Jungeun [1 ]
Bandukwala, Hozefa S. [1 ]
Chavez, Lukas [1 ]
Aijo, Tarmo [1 ,2 ]
Pastor, William A. [1 ]
Segal, Matthew F. [1 ]
Li, Huiming [3 ,4 ]
Koh, Kian Peng [3 ,4 ]
Lahdesmaki, Harri [2 ]
Hogan, Patrick G. [1 ]
Aravind, L. [5 ]
Rao, Anjana [1 ,3 ,4 ,6 ]
机构
[1] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA
[2] Aalto Univ, Sch Sci, Dept Informat & Comp Sci, FI-00076 Aalto, Finland
[3] Harvard Univ, Sch Med, Boston, MA 02115 USA
[4] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA
[5] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA
[6] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
CPG ISLANDS; 5-HYDROXYMETHYLCYTOSINE CONTENT; DNA; BINDING; DIFFERENTIATION; COMPLEX; DATABASE; PATHWAY; RINF;
D O I
10.1038/nature12052
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
TET (ten-eleven-translocation) proteins are Fe(II)- and alpha-ketogluta-rate-dependent dioxygenases(1-3) that modify the methylation status of DNA by successively oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine(1,3-5), potential intermediates in the active erasure of DNA-methylation marks(5,6). Here we show that IDAX (also known as CXXC4), a reported inhibitor of Wnt signalling(7) that has been implicated in malignant renal cell carcinoma(8) and colonic villous adenoma(9), regulates TET2 protein expression. IDAX was originally encoded within an ancestral TET2 gene that underwent a chromosomal gene inversion during evolution, thus separating the TET2 CXXC domain from the catalytic domain. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA and interacts directly with the catalytic domain of TET2. Unexpectedly, IDAX expression results in caspase activation and TET2 protein downregulation, in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits TET2 to DNA before degradation. IDAX depletion prevents TET2 downregulation in differentiating mouse embryonic stem cells, and short hairpin RNA against IDAX increases TET2 protein expression in the human monocytic cell line U937. Notably, we find that the expression and activity of TET3 is also regulated through its CXXC domain. Taken together, these results establish the separate and linked CXXC domains of TET2 and TET3, respectively, as previously unknown regulators of caspase activation and TET enzymatic activity.
引用
收藏
页码:122 / +
页数:7
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