# Role of TET dioxygenase associated immune mechanisms in cardiac injury and repair

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2021 · $431,748

## Abstract

Project Summary/ Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is defined as an expansion of somatic hematopoietic
blood cell clone in individual without hematological disorders. Recent exome sequencing identified
hematopoietic stem and progenitor cells (HSPCs) with frequent mutations of epigenetic regulators (e.g., the
DNA methylcytosine dioxygenase TET2) that exhibited growth advantage with clonal expansion during aging.
Interestingly, CHIP individuals with somatic TET2 mutations tend to have high risk of coronary cardiovascular
diseases (CVD). This discovery heralds the advent of a molecular era in the dissection of novel pathogenic
mechanisms underlying CHIP-CVD convergence. In animal studies that mimic clonal hematopoiesis, Tet2 LOF
has been found to accelerate atherosclerosis and heart failure. While these studies provided detailed
phenotypic characterizations, the underlying molecular mechanisms and the causal relations between TET2
LOF in CHIP and increased CVD risk remain largely unresolved. The PI’s laboratory has developed a set of
unique tools to address this critical clinically-relevant knowledge gap, including (i) tissue specific Tet2-deficient
mouse models (specific ablation of Tet2 in the myeloid lineage or in HSPCs) with reporter genes to enable
real-time lineage tracing in vivo during cardiac injury; and (ii) dCas9 based epigenome editing tools that allow
the interrogation of causal effects between epigenotypes and phenotypes. The team proposes to test the
hypothesis that Tet2 controls the activity of enhancers that regulate the expression of key genes required for
maintaining the proper function of monocytes/ macrophages in the reparative response to ischemic injury (e.g.,
myocardial infarction or MI). Aim 1 will address how Tet2 loss impairs myeloid cells and HSPCs that actively
participate in the post-MI cardiac repair process. Aim 2 will address how Tet2 deficiency disrupts enhancer
activities in key genes that are essential for proinflammatory to reparative monocyte conversion, thereby
perturbing the biphasic post-MI response of monocyte to compromise timely resolution of inflammation and
cardiac repair. The idea of restoring Tet2/5hmC function will be further tested to intervene post-MI tissue repair.
This study introduces a new dimension to dissect CVD pathogenesis by focusing on the interplay between the
cardiovascular system and the immune-hematopoietic system. Completion of this project is anticipated to yield
novel insights on how somatic TET2 mutations-associated clonal hematopoiesis increases the risk of
cardiovascular disease (CVD) and impairs cardiac function under stress. More clinically relevant, discoveries
made in this study are also expected to establish the preclinical rationale for targeting defective epigenetic
regulators to prevent and treat CVD.

## Key facts

- **NIH application ID:** 10143286
- **Project number:** 5R01HL146852-03
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Yun Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $431,748
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143286

## Citation

> US National Institutes of Health, RePORTER application 10143286, Role of TET dioxygenase associated immune mechanisms in cardiac injury and repair (5R01HL146852-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10143286. Licensed CC0.

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