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Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):E8267-E8276. doi: 10.1073/pnas.1617802113. Epub 2016 Dec 5.

Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling.

Author information

1
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
2
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
3
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093.
4
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093; arao@lji.org syevans@ucsd.edu.
5
Department of Medicine, University of California at San Diego, La Jolla, CA 92093.
6
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; arao@lji.org syevans@ucsd.edu.
7
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093.
8
Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093.

Abstract

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.

KEYWORDS:

DNA demethylation; TET methylcytosine oxidases; Wnt signaling; mouse embryonic stem cells; neuromesodermal progenitors

PMID:
27930333
PMCID:
PMC5187696
DOI:
10.1073/pnas.1617802113
[Indexed for MEDLINE]
Free PMC Article

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