# Mechanistic modeling of epigenetic modifier mutations in human pluripotent stem cell-derived immune cells

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $253,500

## Abstract

PROJECT SUMMARY
Clonal hematopoiesis of indeterminate potential (CHIP) refers to the presence of expanded blood cell clones
with one or more somatic mutations without other hematologic abnormalities. CHIP is common in the elderly,
affecting more than 10% of individuals over 65 years. CHIP is associated with a 10-fold increase risk of
hematologic malignancies and a doubled risk of atherosclerotic cardiovascular disease, contributing to an
increase in all-cause mortality. The two most commonly mutated genes in CHIP are DNMT3A and TET2, both
of which encode epigenetic modifiers. Recent studies have found evidence of increased inflammation and
worsened atherosclerosis when the murine ortholog of TET2 was perturbed in myeloid cells in vivo. However,
the specific epigenetic mechanism underlying this phenotype and whether DNMT3A and TET2 mutations
target the same biological pathway are unclear. Furthermore, it remains unexplained why loss-of-function
mutations in DNMT3A and TET2 have shared a clinical outcome despite the two genes encode enzymes with
opposite biochemical functions (DNA methylation vs. de-methylation). To address this knowledge gap, we
developed human pluripotent stem cell (hPSC)-derived macrophage models of DNMT3A- and TET2-
haploinsufficiency. hPSC-derived macrophages are inexhaustible, scalable, and amenable to genetic
manipulation, offering a powerful in vitro model well-suited for mechanistic studies. In this proposal, we
propose the use of this model to (1) define unique and shared epigenetic features of DNMT3A and TET2
haploinsufficiency, and (2) identify transcription factors driving altered immune gene expression in DNMT3A-
and TET2-haploinsufficient immune cells. This project is built on our previous work, and we anticipate that
findings from this study will guide future studies on targeting an epigenetic vulnerability shared between
DNMT3A- and TET2-mutated cells as well as mechanistic studies on other drivers of CHIP.

## Key facts

- **NIH application ID:** 10437235
- **Project number:** 1R21AI164367-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Minji Byun
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $253,500
- **Award type:** 1
- **Project period:** 2022-02-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437235

## Citation

> US National Institutes of Health, RePORTER application 10437235, Mechanistic modeling of epigenetic modifier mutations in human pluripotent stem cell-derived immune cells (1R21AI164367-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10437235. Licensed CC0.

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