Hematopoietic stem and progenitor cells (HSPCs) differentiate from specialized endothelial cells in the embryo called hemogenic endothelium (HE). The transcription factor Runx1 is required for the specification of hemogenic endothelium and for the endothelial to HSPC transition to occur. However, how Runx1 does so is poorly understood. Our goal is to apply systems biology approaches to study the transcriptional regulatory network controlling hemogenic endothelial specification, including the role of Runx1, additional transcription factors that cooperate with Runx1, and the order of regulatory events that promote the process. These studies will not only increase our understanding of the normal developmental process of HSPC formation, but will help guide attempts to generate hematopoietic stem cells (HSCs) from endothelial cells, ES, or iPS cells for the treatment of disease.
In Aim 1, we will identify Runx1 target genes in embryonic endothelial cells that are competent to respond to Runx1, and examine the genome-wide chromatin modifications and gene expression changes that take place when Runx1 binds its target genes.
In Aim 2, we will develop an advanced graph-theoretic method to identify key TFs that cooperate with Runx1 in embryonic endothelial cells to induce HE and form blood. We will validate the candidate TFs by determining their ability to cooperate with Runx1 to induce fetal endothelial cells to undergo endothelial to HSPC transition and form blood.

Public Health Relevance

Bone marrow transplantation is a life-saving procedure for many patients with malignant and nonmalignant hematologic disease, including immune deficiency. Unfortunately not every patient has a suitable donor. The ability to produce hematopoietic stem cells (HSCs) from patient-derived iPS cells would solve this problem. We believe that understanding how HSCs form in the embryo, and having landmarks that will allow us to identify HSCs at various stages of formation is necessary if we are to successfully produce them in vitro.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD089245-03
Application #
9701259
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Coulombe, James N
Project Start
2017-08-21
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19146
Yzaguirre, Amanda D; Howell, Elizabeth D; Li, Yan et al. (2018) Runx1 is sufficient for blood cell formation from non-hemogenic endothelial cells in vivo only during early embryogenesis. Development 145:
Gao, Long; Uzun, Yasin; Gao, Peng et al. (2018) Identifying noncoding risk variants using disease-relevant gene regulatory networks. Nat Commun 9:702