Tet-mediated DNA demethylation regulates specification of hematopoietic stem and progenitor cells during mammalian embryogenesis

Liyang Ma, Qin Tang, Xin Gao, Joun Lee, Run Lei, Masako Suzuki, Deyou Zheng, Keisuke Ito, Paul S. Frenette, Meelad M. Dawlaty

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Ten-eleven translocation (Tet) enzymes promote DNA demethylation by oxidizing 5-methylcytosine. They are expressed during development and are essential for mouse gastrulation. However, their postgastrulation functions are not well established. We find that global or endothelial-specific loss of all three Tet enzymes immediately after gastrulation leads to reduced number of hematopoietic stem and progenitor cells (HSPCs) and lethality in mid-gestation mouse embryos. This is due to defects in specification of HSPCs from endothelial cells (ECs) that compromise primitive and definitive hematopoiesis. Mechanistically, loss of Tet enzymes in ECs led to hypermethylation and down-regulation of NFκB1 and master hematopoietic transcription factors (Gata1/2, Runx1, and Gfi1b). Restoring Tet catalytic activity or overexpression of these factors in Tet-deficient ECs rescued hematopoiesis defects. This establishes Tet enzymes as activators of hematopoiesis programs in ECs for specification of HSPCs during embryogenesis, which is distinct from their roles in adult hematopoiesis, with implications in deriving HSPCs from pluripotent cells.

Original languageEnglish (US)
Article numbereabm3470
JournalScience Advances
Volume8
Issue number9
DOIs
StatePublished - Mar 2022

ASJC Scopus subject areas

  • General

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