# The role of DNMT3A in gene regulation and stem cell expansion

> **NIH NIH K00** · STANFORD UNIVERSITY · 2020 · $89,397

## Abstract

PROJECT SUMMARY 
DNA methylation is an epigenetic modification that plays a key role in regulating stem cells, 
development and many diseases. Abnormal DNA methylation has been observed in cancer for more 
than two decades, with many investigations focusing on promoter hypermethylation, which silences 
tumor suppressor genes. Additionally, DNMT3A, one of de novo DNA methyltransferases, is 
frequently mutated in a spectrum of hematological malignancies. Our lab has demonstrated that 
Dnmt3a loss impairs hematopoietic stem cell (HSC) differentiation, while expanding HSC numbers in 
bone marrow, suggesting DNMT3A may have a role in tumorigenesis and stem cell regulation. 
However, DNA methylation profiling of leukemia patient samples shows DNA methylation correlates 
poorly with gene expression across the genome, highlighting our limited understanding of the specific 
functions of DNA methylation. Recent studies using a murine model of the most frequent DNMT3A 
mutation in hematological malignancies, DNMT3AR882, demonstrated that DNMT3AR882 cooperates 
with FLT3-­ITD and NPM1c mutations to contribute to leukemic transformation. Nevertheless, our 
knowledge of which remaining DNMT3A mutations lead to leukemogenesis and the mechanisms by 
which they contribute to cancer formation remains lacking. Therefore, the long-­term goal of the 
proposed research is to understand how DNMT3A affects gene regulation in cancer, and how 
DNMT3A mutants predispose stem cell expansion. In Aim 1, I established a novel DNA epigenome 
editing tool (dCas9-­SunTag-­DNMT3A system) to investigate the causal relationship between DNA 
methylation and gene expression. Using pan-­cancer analysis of genome-­wide profiles, we have 
identified DNA hypermethylation occurring in the gene-­body regions of canyons (broad and 
undermethylated regions) with activation of corresponding gene expression. In Aim 2, using a 
Dnmt3a mutant murine model I developed, I will elucidate the role of one Dnmt3a mutant in priming 
stem cell expansion. The findings from this proposed research will shed the light on abnormal DNA 
methylation in cancer and molecular mechanisms of DNMT3A-­associated malignancies. Little is 
known about how mutations in epigenetic modifiers affect the 3D genomic structure in cancer. 
Therefore, in Aim 3, I plan to use my postdoctoral studies to understand how epigenetic modifiers 
shape the genomic landscape in cancer and their underlying mechanism. This training program is 
tailored to give me a comprehensive education in basic science research that will be extremely useful 
in achieving my long-­term career goal of becoming an independent cancer researcher.

## Key facts

- **NIH application ID:** 10073657
- **Project number:** 4K00CA222736-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Yung-Hsin Huang
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $89,397
- **Award type:** 4N
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073657

## Citation

> US National Institutes of Health, RePORTER application 10073657, The role of DNMT3A in gene regulation and stem cell expansion (4K00CA222736-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10073657. Licensed CC0.

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