Overlapping Requirements for Tet2 and Tet3 in Normal Development and Hematopoietic Stem Cell Emergence

• Published in: Cell reports (Cambridge) 2015-08, Vol.12 (7), p.1133-1143
• Main Authors: Li, Cheng, Lan, Yahui, Schwartz-Orbach, Lianna, Korol, Evgenia, Tahiliani, Mamta, Evans, Todd, Goll, Mary G.
• Format: Article
• Language: English
• Subjects: Animals; Dioxygenases - genetics; Dioxygenases - metabolism; Embryonic Development; Endothelial Progenitor Cells - cytology; Endothelial Progenitor Cells - metabolism; Gene Expression Regulation, Developmental; Hematopoiesis; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Receptors, Notch - metabolism; Signal Transduction; Transcription Factors - metabolism; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.07.025

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. [Display omitted] •Tet2 and Tet3 are the major 5-methylcytosine dioxygenases in the zebrafish embryo•Tet2 and Tet3 have overlapping requirements in hematopoietic stem cell emergence•Loss of Tet2/3 compromises expression of the gata2b/scl/runx1 hematopoietic program•Notch signaling in the hemogenic endothelium is dependent on Tet2/3 The Tet proteins comprise a family of dioxygenases that convert 5-methylcytosine to 5-hydroxymethylcytosine. Li et al. identify Tet2 and Tet3 as the major 5-methylcytosine dioxygenases in the zebrafish embryo and uncover an overlapping requirement for Tet2 and Tet3 in hematopoietic stem cell emergence.