# The 3D-Structures of the Pre-Pro-B and Pro-B Cell Genomes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $387,500

## Abstract

During the previous grant cycle we demonstrated that non-coding transcription orchestrates chromatin
folding and compartmentalization to specify T cell fate. Briefly, we identified a non-coding RNA named
ThymoD (thymocyte differentiation factor) located 20 kbp upstream of the Bcl11b enhancer. ThymoD-
deficient mice displayed a defect at the onset of T cell development and developed lymphoid
malignancies. We found ThymoD acts to reposition the Bcl11b enhancer from the lamina into the
nuclear interior. The repositioning brings the Bcl11b enhancer and promoter into a single loop domain to
permit efficient enhancer-promoter communication and activation of Bcl11b expression. This process
involves multiple steps: (i) CTCF occupancy across the ThymoD locus and the Bcl11b promoter region,
(ii) activation of cohesin-dependent looping to juxtapose the enhancer and promoter into a single loop
domain that is anchored by CTCF sites in the ThymoD locus and the Bcl11b promoter region, (iii)
repositioning the enhancer from a heterochromatic to an euchromatic environment and (iv) activation of
Bcl11b expression and specification of T cell fate. Here we propose to continue these studies. We would
describe in molecular terms how ThymoD orchestrates T cell fate. Specifically, we would examine
whether and how CTCF occupancy and cohesin-dependent looping orchestrates chromatin folding and
compartmentalization to bring the enhancer and promoter regions into a single loop domain. We would
track Bcl11b locus topology during cohesin loss and cohesin recovery at high spatial and temporal
resolution. We would examine how cohesin mediated loop extrusion directs compartmentalization,
assembles the Bcl11b loop domain and induces a T-lineage specific program of gene expression. Taken
together, these studies would reveal how non-coding transcription induced loop extrusion directs
enhancer-promoter communication with great specificity to specify T cell fate.

## Key facts

- **NIH application ID:** 10390331
- **Project number:** 5R01AI100880-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** CORNELIS MURRE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2012-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390331

## Citation

> US National Institutes of Health, RePORTER application 10390331, The 3D-Structures of the Pre-Pro-B and Pro-B Cell Genomes (5R01AI100880-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10390331. Licensed CC0.

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