# Role of Tet enzymes in embryonic hematopoiesis

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $554,820

## Abstract

ABSTRACT
The central objective of this proposal is to establish how Tet enzymes regulate the specification of blood cells
from endothelial cells during embryonic hematopoiesis, and from pluripotent stem cells in vitro. During embryo-
genesis, hematopoietic stem and progenitor cells (HSPCs) emerge from endothelial cells (ECs) in the arterial
vasculature. A sub-population of ECs undergo an endothelial-to-hematopoietic transition (EHT) to specify
hemogenic endothelial cells (HECs), which then give rise to HSPCs. This specification of ECs to HECs and to
HSPCs is guided by timely expression of hematopoietic genes involving the Runx, Gata and Gfi1 family of
transcription factors. While the developmental origins of hematopoietic cells are broadly defined, the molecular
mechanisms underlying blood formation are poorly understood. A major gap in the field has been how
epigenetic paradigms such as DNA methylation/demethylation regulate activation of hematopoietic programs in
ECs to allow for specification of HECs and formation of HSPCs. DNA methylation, a major modification that
silences genes, is deposited by the DNA methyltransferases and removed by the Tet DNA demethylases. Tet
enzymes are dynamically expressed during development and in many hematopoietic cell types. We have
developed two mouse models that allow for deletion of Tets temporally (post-gastrulation) as well as spatially
(in the endothelial lineage only) during embryogenesis. Using these models, we have recently shown that Tet
enzymes are essential for activation of hematopoietic-specific gene expression programs in ECs, and are
required for embryonic hematopoiesis in mice; functions that are distinct from the roles of Tet enzymes in adult
hematopoiesis. While these findings define a requirement for Tets in emergence of HSPCs from ECs, it is yet
to be established (1) how Tets specifically regulate EC-to-HEC commitment, (2) how Tet-mediated DNA
demethylation activate hematopoietic programs, (3) How are Tets recruited to hematopoietic enhancers, and
(4) whether Tets regulate and enhance derivation of HSPCs from pluripotent stem cells. We hypothesize that
Tet enzymes are required for EC-to-HEC transition where Tet-mediated demethylation in ECs is
essential for activation of hematopoietic enhancers. We also postulate that Tets regulate derivation of
HSPCs from pluripotent stem cells in vitro. We propose two aims. Aim 1 will define the requirements of Tet
enzymes in specification of HECs/HSPCs from ECs during embryonic hematopoiesis in vivo, and from mouse
embryonic stem cells in vitro. Aim 2 will establish how Tets are recruited to hematopoietic enhancers where
they demethylate and activate enhancers to promote transcription factor binding and expression of hemato-
poiesis programs. Our findings will establish Tets as major epigenetic regulators of hematopoietic lineage
specification in vivo and in vitro. It will inform on epigenetic basis of blood formation with implications in
treatment of bl...

## Key facts

- **NIH application ID:** 10843619
- **Project number:** 1R01HL172730-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Meelad Dawlaty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $554,820
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843619

## Citation

> US National Institutes of Health, RePORTER application 10843619, Role of Tet enzymes in embryonic hematopoiesis (1R01HL172730-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10843619. Licensed CC0.

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