# Critical role of TCF-1 on the epigenetic identity of memory T cells

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $451,689

## Abstract

The goal of this proposal is to study the role of transcription factor TCF-1 in determining the epigenetic identity
of memory CD8+ T cells. Our adaptive immune system has evolved a unique capacity to remember a pathogen
through the generation of memory T cells, which protect the host in the event of reinfection. A better
understanding of memory T cell differentiation is crucial for developing strategies to limit T cell responses in
organ transplantation or enhance T cell responses during chronic infections. Although it is known that the
transcription factor TCF-1 is required for memory CD8+ T cell function, the mechanisms through which this
protein controls memory T cell fate remain unclear. Recently, we discovered that a mechanism through which
TCF-1 controls the development of T cells relates to its unprecedented ability to create the chromatin
accessibility landscape of naïve T cells. We found that TCF-1 is selectively enriched at genomic regions that
become accessible at the earliest stages of development and is required for the accessibility of these
regulatory elements. At the single-cell level, TCF-1 can dictate a coordinate opening of chromatin in T cells.
Moreover, ectopic TCF-1 can directly erase repressive chromatin marks in non-T cells, generating de novo
open chromatin and inducing the expression of T cell genes. While our recent data determined the novel role
of TCF-1 on the epigenome during T cell development, our findings also raised another critical question: what
is the role of TCF-1 on the epigenetic identity of memory T cells? We hypothesize that TCF-1 in cooperation
with transcription factor partners defines the epigenetic landscape of memory T cells. Our new preliminary data
further indicate that TCF-1 expression post T cell activation in vitro can lead to gains in chromatin accessibility
at pro-memory genes. However, it remains unclear if TCF-1 expression in T cells responding to an infection
can create the epigenetic identity of memory T cells. The domains of TCF-1 required for targeting the
chromatin and its potential cooperating factors also remain unknown. How TCF-1 dependent changes on the
epigenome relate to pro-memory genes needs to be defined. To answer these questions, we will interrogate
the effect of TCF-1 and its potential partners on the chromatin state and accessibility of CD8+ T cells in vitro.
Using the state-of-the-art tools, we will generate the map of TCF-1 dependent 3D genome organization and
define how changes on the epigenome relate to memory genes. We will further translate these findings in vivo
exploiting single-cell epigenomic, transcriptomic, and flow cytometry assays. The expected outcome of this
proposal is a detailed understanding of the fundamental interaction between TCF-1 and the chromatin in
peripheral T cells which can be exploited to devise combination therapies including epigenetic editing to
selectively alter T cell fate at will.

## Key facts

- **NIH application ID:** 10320935
- **Project number:** 5R01HL145754-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Golnaz Vahedi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $451,689
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320935

## Citation

> US National Institutes of Health, RePORTER application 10320935, Critical role of TCF-1 on the epigenetic identity of memory T cells (5R01HL145754-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10320935. Licensed CC0.

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