title: Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling.
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.
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yue
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: William A
authors.initials: WA
authors.lastname: Pastor
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Lizhu
authors.initials: L
authors.lastname: Lin
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Romain
authors.initials: R
authors.lastname: Georges
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093; arao@lji.org syevans@ucsd.edu.|Department of Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; arao@lji.org syevans@ucsd.edu.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.|Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093.|Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D053595:Embryonic Stem Cells / Q000166:cytology; D044127:Epigenesis, Genetic; D055106:Genome-Wide Association Study; D008648:Mesoderm / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D054258:Neural Plate / Q000196:embryology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse
keywords: DNA demethylation; TET methylcytosine oxidases; Wnt signaling; mouse embryonic stem cells; neuromesodermal progenitors