期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：51
页码：E8267-E8276
DOI：10.1073/pnas.1617802113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMethylation of cytosine bases in DNA is an epigenetic modification that influences gene expression. TET (ten-eleven translocation)-family dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and additional oxidized methylcytosines in DNA. Here, we show that both Tet3- and Tet1/2/3-deficient mouse ES cells showed impaired neural conversion, with skewing toward cardiac mesoderm. Genome-wide analyses showed that Tet3 mediates cell-fate decisions by inhibiting Wnt signaling. Consistent with these findings, Wnt signaling was hyperactivated in Tet1/2/3-deficient embryos, leading to aberrant differentiation of bipotent neuromesodermal progenitors into mesoderm at the expense of neuroectoderm. Our data demonstrate a key role for TET proteins in modulating Wnt signaling and establishing the proper balance between neural and mesoderm cell fate determination. TET-family dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and oxidized methylcytosines in DNA. Here, we show that mouse embryonic stem cells (mESCs), either lacking Tet3 alone or with triple deficiency of Tet1/2/3, displayed impaired adoption of neural cell fate and concomitantly skewed toward cardiac mesodermal fate. Conversely, ectopic expression of Tet3 enhanced neural differentiation and limited cardiac mesoderm specification. Genome-wide analyses showed that Tet3 mediates cell-fate decisions by inhibiting Wnt signaling, partly through promoter demethylation and transcriptional activation of the Wnt inhibitor secreted frizzled-related protein 4 (Sfrp4). Tet1/2/3-deficient embryos (embryonic day 8.0-8.5) showed hyperactivated Wnt signaling, as well as aberrant differentiation of bipotent neuromesodermal progenitors (NMPs) into mesoderm at the expense of neuroectoderm. Our data demonstrate a key role for TET proteins in modulating Wnt signaling and establishing the proper balance between neural and mesodermal cell fate determination in mouse embryos and ESCs.
