# Transcriptional and epigenetic heterogeneity of stem/progenitor cells

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $422,831

## Abstract

Project Summary/Abstract
 All mature blood cells are derived from rare hematopoietic stem and progenitor cells (HSPCs) that reside in
the adult bone marrow. Evidence shows that proper gene expression in HSPCs is essential for maintenance of
homeostasis. Moreover, recent work suggests that progenitor cells may be as important as hematopoietic stem
cells (HSC) in maintaining steady-state blood cell production and establishes a new level of complexity in blood
cell production. Several transcription factors are critical for the formation and function of HSPCs, and for the
differentiation to specific blood lineages. However, following hematologic injuries that reduce
blood cell numbers, such as chemotherapy or toxic insult, a slow HSC response can result in life threatening
complications from infection, bleeding, and anemia. Furthermore, malfunctioning HSPCs through dysregulated
transcription factor expression can result in bone marrow failure or malignancies. Cell isolation through flow
cytometry using specific surface markers has significantly refined the HSPC population. However, since
tissues and populations are rarely homogeneous and consist of numerous distinct subsets, it has become
increasingly clear that studying bulk populations of cells provides only limited knowledge, while interrogation of
individual cells would provide insight into biological processes masked at the population level. Therefore, it is
important to identify the molecular events regulating HSPC self-renewal, proliferation, and differentiation during
both steady-state and stress hematopoiesis at the single cell level. Additionally, the hereditable properties of
individual clones suggested that some HSPCs are imbalanced with respect to myeloid versus lymphoid cell
potential as well as cell cycle status that can alters their reconstitution potential. Our proposal will use droplet-
based Barcoding and Analysis of Single Cells (dBASC) to discover distinct transcriptional and epigenetic
clonality of the earliest events in adult hematopoiesis. Functional heterogeneity of HSPCs based on analysis of
self-renewal and differentiation at a clonal level has been appreciated for some time through cell
transplantation assays but our collaborators, Camargo, Scadden, and Zon and have taken this a step further to
uncover steady-state clonal hematopoiesis. The transcriptional network within HSPCs to promote self-renew is
maintained through several well-characterized pathways. Together with Dr. Orkin’s single cell RT-PCR
approach, we will validate the importance of transcriptional and epigenetic regulation on HSPC clonality. By
studying the transcriptional network that regulate self-renewal, stress and clonal hematopoiesis, our unique
single cell approach will provide an important step toward our fundamental understanding of biology of HSPCs
and progenitors.

## Key facts

- **NIH application ID:** 9929654
- **Project number:** 5P01HL131477-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** DANIEL G TENEN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,831
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929654

## Citation

> US National Institutes of Health, RePORTER application 9929654, Transcriptional and epigenetic heterogeneity of stem/progenitor cells (5P01HL131477-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9929654. Licensed CC0.

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