# Determinants of epigenetic inheritance in human stem cell fate decisions

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2024 · $441,250

## Abstract

Project summary
 In hematopoietic stem cells (HSCs), the epigenome confers self-renewal and differentiation functions
wherein inheritance of HSC chromatin states is persistent across cell cycles. My postdoctoral studies focused
on a fundamental epigenetic feature involving the local recycling of pre-existing, parental nucleosomes, which
showed that repressed, but not active, chromatin domains are inherited across DNA replication. While
identifying the histone chaperone(s) that facilitate the inheritance of repressed chromatin domains in mouse
embryonic stem cells, I discovered that nucleophosmin, NPM1, plays an essential role in this process. NPM1 is
a histone chaperone whose genetic mutation and rearrangement are found in ~30% of all adult AML, however
its function in normal hematopoiesis remains unknown. Furthermore, key questions persist on the inheritance
of H3K27me chromatin domains, such as what brings NPM1 and the polycomb repressive complex 2 (PRC2)
to the DNA replication fork during S-phase, how are polycomb chromatin domains inherited in the developing
immune system, and whether parental nucleosome segregation has a role in the precise balancing between
self-renewal and differentiation capacities that shape a hematopoietic cascade. In this proposal, my group will
identify the molecular basis for constructing the heritable human epigenome of HSCs and discover the
chromatin dynamics that provide HSCs the ability to both self-renew and differentiate. We will use in vitro
human induced pluripotent stem cells and differentiate them to derive a hematopoietic progenitor cell fate.
Using this system, we will conduct cutting age genome engineering, proteomics, and imaging technologies to
discover the function of histone chaperones and polycomb in constructing the heritable epigenome of HSCs.

## Key facts

- **NIH application ID:** 10891483
- **Project number:** 5R35GM151179-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Thelma Escobar
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,250
- **Award type:** 5
- **Project period:** 2023-07-20 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891483

## Citation

> US National Institutes of Health, RePORTER application 10891483, Determinants of epigenetic inheritance in human stem cell fate decisions (5R35GM151179-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10891483. Licensed CC0.

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