# Identification of a CSR specific checkpoint

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $199,875

## Abstract

ABSTRACT
Humoral immune responses require the diversification of the Ig repertoire by means of antigen
receptor rearrangements. The mouse Igh locus spans 2.9 Mb within which are ~100 functional
VH gene segments that participate in V(D)J recombination and eight CH genes that are used
during class switch recombination (CSR). Activation induced deaminase (AID) is essential for
both immunoglobulin somatic hypermutation and CSR in mature B cells. CSR requires
transcription and induction of DNA double strand breaks (DSBs) that must synapse over long
genomic distances to facilitate intra-chromosomal rearrangement. The Igh locus assumes specific
chromatin topologies that facilitate CSR and these may vary at different stages of B cell
development. In new studies we have examined the relationship between developmentally
regulated higher-order chromatin structure, gene expression and recombination using
chromosome conformation capture based approaches in combination with functional assessment
of CSR. We discovered an unexpectedly high frequency of chromatin interactions among
downstream CH genes. This led us to postulate that downstream S regions could recombine with
each other. Our studies confirmed this hypothesis and led to a revision of the model for CSR.
These studies stimulated us to search for B cell subsets that are actively engaged in CSR.
Unexpectedly, B cells that are engaged in CSR become BCR negative and reside in the G1 phase
of the cell cycle suggesting the presence of a DNA double strand break checkpoint.
Furthermore, BCR- cells dynamically transition to IgM+ and then re-cycle to BCR-. Here we
propose to profile the transcriptome of B cell subsets engaged in CSR and determine their cell
fate branch point. These studies are very important since BCR negative B cells will be
unresponsive to exogenous antigen and this has important implications for B cell activation.

## Key facts

- **NIH application ID:** 10198743
- **Project number:** 5R21AI151892-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Amy L Kenter
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $199,875
- **Award type:** 5
- **Project period:** 2020-06-19 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198743

## Citation

> US National Institutes of Health, RePORTER application 10198743, Identification of a CSR specific checkpoint (5R21AI151892-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10198743. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*