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

被引：65

作者：

Li, Cheng ^{[1
,2
]}

Lan, Yahui ^{[3
]}

Schwartz-Orbach, Lianna ^{[1
]}

Korol, Evgenia ^{[4
]}

Tahiliani, Mamta ^{[4
]}

Evans, Todd ^{[3
]}

Goll, Mary G. ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA

[2] Cornell Univ, Weill Cornell Grad Sch Med Sci, Program Biochem & Struct Biol Cell & Dev Biol & M, New York, NY 10065 USA

[3] Weill Cornell Med Coll, Dept Surg, New York, NY 10065 USA

[4] NYU, Sch Med, Skirball Inst Biomol Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA

来源：

CELL REPORTS | 2015年 / 12卷 / 07期

关键词：

MEDIATED 5-METHYLCYTOSINE OXIDATION; DNA DEMETHYLATION; HEMOGENIC ENDOTHELIUM; AORTIC ENDOTHELIUM; ZEBRAFISH MODEL; MAMMALIAN DNA; 5MC OXIDATION; SELF-RENEWAL; DIFFERENTIATION; GENE;

D O I：

10.1016/j.celrep.2015.07.025

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1133 / 1143

页数：11

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