# BRWD1 and the molecular regulation of humoral immunity

> **NIH NIH F32** · UNIVERSITY OF CHICAGO · 2020 · $33,723

## Abstract

PROJECT SUMMARY
Our laboratory recently demonstrated that the lineage-restricted BROMO and WD40 domain containing
epigenetic reader BRWD1 opens Igκ and enables assembly of RAG proteins at Jκ. I now report that BRWD1
has a much broader role in late B cell development. In the bone marrow, BRWD1 reshaped chromatin
landscape by closing enhancers of genes expressed early in B cell development and opening those of genes
expressed in late stages. In the absence of BRWD1, over 7000 genes were aberrantly expressed. While many
of these genes are normally expressed in earlier developmental stages, many are also part of the germinal
center (GC) transcription program. BRWD1 is first expressed in small pre-B cells. However, Brwd1 expression
was much higher in naïve follicular (FO) and highest in day 12 GC B cells. These data suggest BRWD1 could
also regulate GC B cell programs. My data in WT GC B cells highly supports this. By using a novel 3-
population gating strategy to isolate dark zone (DZ), light zone (LZ), and newly identified population grey zone
(GZ), I found large transcriptional and genome accessibility differences between DZ and LZ cells. The GZ is
also unique from DZ and LZ B cells based on transcription and genome accessibility, suggesting it may contain
a novel GC B cell subpopulation(s). In LZ cells, BRWD1 is expressed in Myc- cells, a transcription factor
repressed by BRWD1. Finally, analysis of genes differentially expressed in GC DZ and LZ, compared to those
differentially regulated by BRWD1 in small pre-B cells, predicted that BRWD1 represses the DZ program and
induces the LZ program. This has immunological implications as immunized mice lacking BRWD1 in GC B
cells exhibited disorganized GCs and severely impaired affinity maturation. Overall, these data suggest
similarities between genetic programs that separate proliferation and Igκ recombination in development and
those that segregate proliferation from selection in GCs. Based on these findings, I hypothesize that by
regulating enhancer accessibility BRWD1 is important to regulate transcriptional programs in novel GC B cell
subsets. Additionally, I hypothesize that by repressing DZ and inducing LZ genetic programs, BRWD1 is critical
for GC-dependent humoral immunity. These hypotheses will be tested in the following Specific Aims:
Aim 1. Define transcriptional regulation of normal germinal center responses.
Aim 2. Determine the role of BRWD1 in adaptive immunity.

## Key facts

- **NIH application ID:** 9899728
- **Project number:** 5F32AI143120-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Domenick Edward Kennedy
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,723
- **Award type:** 5
- **Project period:** 2018-12-01 → 2020-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899728

## Citation

> US National Institutes of Health, RePORTER application 9899728, BRWD1 and the molecular regulation of humoral immunity (5F32AI143120-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899728. Licensed CC0.

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