# Molecular and physical mechanisms that underpin the αβ versus γδ T cell fate decision

> **NIH NIH P01** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $387,631

## Abstract

PROJECT SUMMARY/ABSTRACT
It is now well established that the onset of T cell development is initiated by the induction of Notch expression.
During the previous grant cycle, we found that this critical step is controlled by the combined activities of E2A
and HEB. Once Notch1 expression is activated, Notch signaling acts in concert with RUNX1, TCF1, E2A and
GATA-3 to activate Bcl11b expression. Bcl11b next acts in concert with E2A to activate a T-lineage specific
gene program. We (with Project 1) also demonstrated that E2A activates the expression of a non-coding
transcript, named ThymoD, to reposition the Bcl11b enhancer from the nuclear lamina to the nuclear interior.
These studies linked E-protein occupancy, non-coding transcription and Bcl11b expression into a common
pathway that orchestrates the αβ versus γδ T cell fate decision. We now aim to describe, in physical and kinetic
terms, Bcl11b locus movement relative to the onset of T cell development. To track genomic interactions in live
lymphoid cells, we have developed a novel strategy. Specifically, we tracked the motion of DNA elements to
visualize VDJ recombination in live B cells using tandem arrays of WT-TET and MUT-TET repressor binding
sites. We propose to use the same strategy to describe in live T cells the trajectories of Bcl11b enhancer-
promoter communication. Specifically, we will examine how Bcl11b enhancer-promoter communication is
suppressed when sequestered at the nuclear lamina prior to commitment to the T cell lineage and after these
loci return to the lamina upon adoption of the γδ T cell fate (with Projects 1 and 3). We will also examine how
E-proteins and Notch signaling modulate Bcl11b enhancer-promoter communication to establish and maintain
αβ T cell identity (with Projects 2 and 3) and how E-proteins, Notch signaling, non-coding transcription and
nuclear repositioning are linked in four-dimensional space to orchestrate αβ T cell fate. Collectively these
studies proposed here would be a first step towards describing the αβ versus γδ T cell fate choice in four-
dimensional space and would not be possible outside of this integrated programmatic effort.

## Key facts

- **NIH application ID:** 9989065
- **Project number:** 5P01AI102853-07
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** CORNELIS MURRE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,631
- **Award type:** 5
- **Project period:** 2014-05-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989065

## Citation

> US National Institutes of Health, RePORTER application 9989065, Molecular and physical mechanisms that underpin the αβ versus γδ T cell fate decision (5P01AI102853-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989065. Licensed CC0.

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