title: Overlapping Requirements for Tet2 and Tet3 in Normal Development and Hematopoietic Stem Cell Emergence.
abstract: The Tet family of methylcytosine dioxygenases (Tet1, Tet2, and Tet3) convert 5-methylcytosine to 5-hydroxymethylcytosine. To date, functional overlap among Tet family members has not been examined systematically in the context of embryonic development. To clarify the potential for overlap among Tet enzymes during development, we mutated the zebrafish orthologs of Tet1, Tet2, and Tet3 and examined single-, double-, and triple-mutant genotypes. Here, we identify Tet2 and Tet3 as the major 5-methylcytosine dioxygenases in the zebrafish embryo and uncover a combined requirement for Tet2 and Tet3 in hematopoietic stem cell (HSC) emergence. We demonstrate that Notch signaling in the hemogenic endothelium is regulated by Tet2/3 prior to HSC emergence and show that restoring expression of the downstream gata2b/scl/runx1 transcriptional network can rescue HSCs in tet2/3 double mutant larvae. Our results reveal essential, overlapping functions for tet genes during embryonic development and uncover a requirement for 5hmC in regulating HSC production.
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program in Biochemistry and Structural Biology, Cell and Developmental Biology, and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lianna
authors.initials: L
authors.lastname: Schwartz-Orbach
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Korol
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Mamta
authors.initials: M
authors.lastname: Tahiliani
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Evans
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: gollm@mskcc.org.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Goll
mesh_terms: D000818:Animals; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D047108:Embryonic Development; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051880:Receptors, Notch; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000596889:TET2 protein, zebrafish; C000608377:TET3 protein, zebrafish; D049308:Dioxygenases