# Manipulating the Stem Cell Epigenome to Improve Bone Marrow Transplantation

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $283,350

## Abstract

ABSTRACT
 Bone marrow transplantation (BMT) is the best-established stem cell therapy, and has been used
successfully in clinical settings for almost 50 years. However, identifying sources of appropriate donor material
for BMT continues to be a limiting factor for many adult patients. Umbilical cord blood (UCB) has become an
increasingly popular donor source because the hematopoietic cells from newborn babies are immunologically
more naïve. This reduces the risk of graft-versus-host-disease (GvHD), and therefore the patient and donor do
not have to be as immunologically compatible. UCB has extended patient access to BMT, especially for
patients of racial and ethnic minorities. Despite multiple advantages of UCB transplant, it is associated with
delayed engraftment and immune reconstitution, leading to a greater risk of infections and graft reject as
compared to bone marrow or peripheral blood grafts from adult donors. This is primarily related to the lower
content of hematopoietic stem cells (HSCs), the functional units of long-term hematopoietic repopulation in
BMT, within individual cord blood units. These caveats have limited the application of UCB transplantation.
There are intense efforts to expand UCB HSC numbers or increase their potency ex vivo, but these studies
have been largely unsuccessful. Here, we propose a novel method to resolve this long-standing problem. In
murine models, we identified a mechanism that prevents chromatin-mediated silencing of HSC self-renewal
genes by antagonizing the epigenetic regulator JARID2, which recruits Polycomb Repressive Complex 2
(PRC2) to catalyze the repressive histone modification of H3K27me3. Here, we will leverage these results to
determine if transient inhibition of JARID2 can be used to increase the number of transplantable HSCs ex vivo,
and improve BMT. Specifically, we hypothesize that JARID2 inhibition will prevent PRC2-mediated
epigenetic repression of self-renewal gene expression programs, thereby expanding the pool of cells
with functional repopulation potential. We will formally investigate this strategy in the following Specific Aim:
  Determine if inhibition of JARID2 can expand functional repopulating cells for bone marrow
 transplant and define the mechanisms
 There are three prongs to our approach; (A) Determine if transient inhibition of JARID2 can expand the pool
of functional HSCs, (B) Identify the protein domains of JARID2 required for PRC2-mediated repression of HSC
self-renewal genes, and (C) Identify trans-activating factors that regulate JARID2 expression for translational
exploitation. The SHINE-II mechanism (PAS-15-168) is dedicated to supporting new research directions in
their early stages. Consistent with this goal, translational BMT research is a completely new area of study for
our lab. But with our experience in epigenetic regulation of HSCs and access to collaborative expertise, we are
poised to make novel contributions to this significant clinical problem. Achieve...

## Key facts

- **NIH application ID:** 9980366
- **Project number:** 5R01DK119231-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Grant Anthony Challen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $283,350
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980366

## Citation

> US National Institutes of Health, RePORTER application 9980366, Manipulating the Stem Cell Epigenome to Improve Bone Marrow Transplantation (5R01DK119231-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9980366. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*