# Topological Control of Antigen Receptor Loci during Lymphocyte Development

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $726,998

## Abstract

ABSTRACT
Gene expression relies on interplay among cis elements, chromatin domains, and genome architecture. The
latter is of intense interest as ~10% of human diseases may arise from defects in genome topology that impact
gene expression. Genomes divide into conserved, Mb-sized topologically associated domains (TADs) that are
further subdivided into cell type-specific loops between promoter and enhancers (regulatory loops) or between
CTCF binding elements (structural loops). In addition, chromatin architecture can be shaped by tissue-specific
boundary elements (BEs) that divide active and inactive regions of transcription. These two types of domains
tend to associate spatially, perhaps through homotypic chromatin interactions. Foundational questions remain
about mechanisms of genome architecture reorganization and its impact on gene expression during cellular
differentiation. Answers to these questions have important implications because disease-associated variants in
the human genome can disrupt CTCF sites or BEs, enabling aberrant communication between enhancers and
alternative promoters that normally partition into separate architectural domains. The co-PIs have approached
relationships between genome topology and gene regulation by focusing on the mouse Tcrb antigen receptor
locus for several reasons, including: (i) it is a physiological model of manageable complexity (ii) its architecture
and transcription are dynamically regulated during T cell development, (iii) it divides into alternating chromatin
domains, (iv) changes in topology and transcription are critical for Tcrb assembly by long-range recombination,
and (v) its recombination center (RC) has a simple regulatory landscape with one enhancer that communicates
with two promoters to initiate all aspects of Tcrb assembly. The PIs' recent collaborations have provided
important clues into the dynamics of Tcrb structure at a low level of resolution, but insights into mechanisms
that sculpt the observed architectural changes are still lacking. These and other data support their hypothesis
that developmental switches between inactive and active Tcrb conformations are orchestrated by tissue- and
stage-specific changes in the binding of CTCF to cornerstone elements and by the transcription status of
individual gene segments, which cooperate to compartmentalize Tcrb into distinct structural domains and drive
homotypic interactions that facilitate long-range Tcrb gene assembly. To test foundational aspects of their
hypothesis, the PIs propose to elucidate detailed topologies of active versus inactive Tcrb loci (Aim 1), assess
whether transcription status and homotypic chromatin interactions shape Tcrb conformations (Aim 2), and
determine mechanisms by which CTCF elements direct Tcrb topology (Aim 3). The co-PIs will monitor multiple
physiological readouts (topology, transcription, chromatin, and recombination) to gain unprecedented insights
into mechanistic relationships among genome architectu...

## Key facts

- **NIH application ID:** 9987498
- **Project number:** 5R01AI130231-04
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** CRAIG H BASSING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $726,998
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987498

## Citation

> US National Institutes of Health, RePORTER application 9987498, Topological Control of Antigen Receptor Loci during Lymphocyte Development (5R01AI130231-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9987498. Licensed CC0.

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