# Modulation of chromatin dynamics to promote transplant survival

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $644,870

## Abstract

Project Summary
Rejection remains a major hurdle to long-term transplant survival, in which Teff cells are prominently
involved. We surmise that besides signals from the TCR, costimulatory and cytokine receptors, targeting the
“T cell epigenome” downstream of T cell activation may represent novel therapeutic opportunities in the
induction of transplant tolerance. Now we have new preliminary data showing that the chromatin in Teff
cells are highly compartmentalized, in that “super enhancers” at accessible chromatin regions appear to
control a Teff cell fate by recruiting a chromatin reader called BRD4. We then developed a Brd4-floxed mice
and showed that conditional deletion of Brd4 in T cells completely abrogated the lethal autoimmune
phenotype in Scurfy mice and produced long-term allograft survival in Brd4f/fCd4-Cre mice. Thus, dissecting
mechanistically how BRD4 epigenetically regulates Teff cells and transplant survival is the central goal of
this proposal. Our working hypothesis is that BRD4 occupancy at the accessible chromatin regions locks
active chromatin modules in an accessible state or triggers reorganization of “super enhancers” into
transcriptionally hyper-active “hotspots” to drive a Teff cell fate. We proposed 3 Aims in this proposal to test
this hypothesis. Aim 1 is to determine whether BRD4 locks “active” chromatin modules in an accessible
state, allowing the formation of 3D chromatin configurations to specify a Teff cell fate, and Aim 2 is to
examine whether BRD4 enables stable SE “hotspots”, allowing Teff cells to establish essential features of
Teff profiles. Aim 3 is to test whether therapeutically targeting BRD4 enables long-term allograft survival in
a heart transplant model. We believe that the proposed studies will uncover new insights and open new
therapeutic opportunities in transplantation. The animal models, tools, and cutting-edge technologies we
have developed in the lab put us in a unique position to carry out the proposed studies.

## Key facts

- **NIH application ID:** 10770319
- **Project number:** 1R01AI179616-01
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Xian Chang Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $644,870
- **Award type:** 1
- **Project period:** 2023-12-06 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770319

## Citation

> US National Institutes of Health, RePORTER application 10770319, Modulation of chromatin dynamics to promote transplant survival (1R01AI179616-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10770319. Licensed CC0.

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