# Genome Architecture in Human Germinal Center B Cell Development, Malignancy, and Somatic Hypermutation

> **NIH NIH U01** · YALE UNIVERSITY · 2021 · $640,693

## Abstract

SUMMARY
During the humoral immune response, somatic hypermutation (SHM) introduces point mutations in
rearranged immunoglobulin (Ig) genes of activated germinal center (GC) B cells. SHM is essential for the
fine-tuning of antibody affinity, the generation of B cells expressing high-affinity antibody, and the efficacy of
many vaccines. Mistargeted SHM activities can lead to mutations and chromosomal translocations that
contribute to the development of B cell lymphoma. Recent studies suggest that the three-dimensional (3D)
organization of the genome regulates SHM targeting and mistargeting. However, it is largely unknown how
the genome is spatially organized across multiple length scales in GC B cell development and lymphoma,
and how 3D genome architecture mechanistically affects the targeting and mistargeting of SHM.
Conventional approaches cannot address these questions in the primary GC tissue environment due to
technical limitations. Here, we propose to apply a new method recently developed by our team, termed
Multiplexed Imaging of Nucleome Architectures (MINA), to primary human tonsil tissue samples and
malignant GC-derived human B cell lymphomas. We will investigate and test the association between SHM
susceptibility and a variety of 3D nucleome architectures, including topologically associating domain (TAD)
architecture, phase separation, and nuclear positioning of genomic regions relative to nuclear lamina,
nucleoli, and nuclear pores. Through targeted genomic perturbations in human B cell lymphomas, we will
test specific hypotheses linking SHM targeting elements to elevated chromatin looping interactions, TAD
phase separation, nuclear pore proximity, and mutation vulnerability. Our study will significantly advance our
understanding of the role of 3D genome architecture and nuclear organization in GC B cells undergoing
SHM in both the developmental and tumorigenesis contexts. We expect this study to establish a new
research paradigm and transform 3D nucleome investigations in immunobiology.

## Key facts

- **NIH application ID:** 10264152
- **Project number:** 5U01CA260701-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** David G. Schatz
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $640,693
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10264152

## Citation

> US National Institutes of Health, RePORTER application 10264152, Genome Architecture in Human Germinal Center B Cell Development, Malignancy, and Somatic Hypermutation (5U01CA260701-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10264152. Licensed CC0.

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