# RNA associated mechanisms for antigen receptor gene diversification during immature B cell development

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $568,537

## Abstract

PROJECT SUMMARY
Background: VDJ recombination, Class switch recombination (CSR) and somatic hypermutation (SHM) are
three B lymphocyte-specific processes that mediate antibody gene diversification. VDJ recombination requires
the DNA double-strand break generation by the recombination activation genes (RAG1 and RAG2) whereas
CSR and SHM require the single-strand DNA break activity of the activation induced deaminase (AID) enzyme.
Both RAG1/2 and AID activities are coupled with noncoding RNA transcription at sites of DNA break/mutation.
The properties of the ncRNAs generated at sites of programmed DNA breaks are poorly characterized in B-
cells. Recently advances in biology have provided compelling evidence that post-transcriptional and co-
transcriptional regulation of chromatin associated noncoding regulatory RNAs expressed from the IgH
locus (here, nomenclatured as VDJ-carRNA) and their modifications may have significant roles in driving B cell
development and function and prevention of THES immunodeficiency, a severe inherited disorder. In this
application, supported by preliminary data generated in our laboratory, we are evaluating the role of VDJ-
carRNA in early B cell development and VDJ recombination.
Objective/Hypothesis: VDJ-carRNAs expressed from the IgH locus of immature B cells are processed by the
RNA exosome complex to promote VDJ recombination via mechanisms that are relevant for RAG enzyme
activity.
Specific aims: Aim 1: Can B cell development be rescued in exosome deficient mice; Aim 2: Are specific RNA
helicases important for B cell development and VDJ recombination?; Aim 3: Do VDJ-carRNAs influence VDJ
recombination efficiency?
Study Design: Using cell lines and mouse models, we will study potential mechanisms by which RNA
exosome and substrate chromatin associated regulatory ncRNAs (VDJ-carRNA) on the IgH locus play roles in
orchestrating VDJ recombination. We will generate direct evidence that in the absence of RNA exosome and
its essential helicase cofactors B cell development is attenuated due to a direct defect in VDJ recombination.
We will use a combination of various genomic and biochemical tools to elucidate the associated mechanisms.
Disease Relevance: B cells are a central component of the adaptive immune response, but also prone to
undergo leukemias and lymphomas when antibody gene diversification processes are not well controlled.
Moreover, B cells deficient in RNA exosome demonstrate trichohepatoenteric (THES) syndrome, a B cell
immune system disease.

## Key facts

- **NIH application ID:** 10996437
- **Project number:** 1R01AI178892-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Uttiya Basu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $568,537
- **Award type:** 1
- **Project period:** 2024-06-24 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996437

## Citation

> US National Institutes of Health, RePORTER application 10996437, RNA associated mechanisms for antigen receptor gene diversification during immature B cell development (1R01AI178892-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10996437. Licensed CC0.

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