# REGULATION OF HEMATOPOIETIC PROGENITORS BY DE NOVO DNA METHYLATION

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $673,301

## Abstract

Project Summary/Abstract
DNA METHYLTRANSFERASE 3A (DNMT3A) has emerged as a key regulator of hematopoiesis. We showed
that loss of DNMT3A inhibited hematopoietic stem cell (HSC) differentiation while favoring self-renewal,
establishing the paradigm through which the myriad effects of somatic DNMT3A mutations in humans are
currently viewed. DNMT3A is the most frequently mutated gene in clonal hematopoiesis (CH) and a critical tumor
suppressor. While the broad importance of DNMT3A is clear, the mechanisms through which it participates in
HSC differentiation remain poorly understood. A major long-term interest of my lab is to unravel the
molecular mechanisms of DNMT3A function. In the previous 4-years of funding, my lab has contributed to
advancing our understanding of DNMT3A in multiple facets, including discovery of immortalization of phenotypic
HSCs with DNMT3A loss, uncovering the complex interactions between DNMT3A and TET1 and TET2,
description of epigenetic alterations with human mosaicism, and DNA methylation canyons as sites of very long-
range interactions. In the next phase, we will build on this work, exploring the mechanisms through which
DNMT3A functions in HSCs. We will dissect the distinct roles of DNMT3A isoforms in regulating HSC
differentiation and gene expression using unique knock-out mice. We will also examine the mechanisms through
which stability of DNMT3A protein is maintained and the impact on hematopoiesis. Our preliminary data indicate
that about 1/3 of DNMT3A mutations that contribute to CH lead to loss of protein stability and we have identified
an E3-ubiquitin ligase complex putatively involved in its turnover. These studies offer the opportunity to modulate
degradation of mutant and WT DNMT3A with potential therapeutic impact. Finally, we will examine the basis of
cell competition of DNMT3A mutants in the context of both bone marrow and during development. Using cells
with different DNMT3A mutations with distinct predicted fitness, we will generate bone marrow chimeras and
investigate the relationship between loss of DNA methylation activity and the degree of competitive advantage.
We will also generate embryo chimeras and examine the contribution of mutant vs WT cells to multiple tissues
and lineages. These studies will reveal fundamental principles governing cell competition and thus insights into
clonal hematopoiesis and stem cell dynamics. Overall, the proposed work will advance our understanding of
clonal dynamics in hematopoiesis and the role of DNMT3A in maintaining proper hematopoiesis. The studies
could ultimately lead to strategies to modulate clonal dynamics in pathologic conditions.

## Key facts

- **NIH application ID:** 10370435
- **Project number:** 5R01DK092883-11
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** MARGARET A. GOODELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $673,301
- **Award type:** 5
- **Project period:** 2011-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370435

## Citation

> US National Institutes of Health, RePORTER application 10370435, REGULATION OF HEMATOPOIETIC PROGENITORS BY DE NOVO DNA METHYLATION (5R01DK092883-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10370435. Licensed CC0.

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