BRWD1 directs B cell epigenetic states required for germinal center initiation, maintenance and function.
5 affiliations
- 1Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA.
- 2AbbVie, Immuno-Oncology Discovery, North Chicago, IL, USA.
- 3Research Informatics Core, University of Illinois at Chicago, Chicago, IL, USA.
- 4Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA. [email protected].
- 5Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA. [email protected].
Abstract
Germinal center (GC) B cells, differentiated from follicular B cells following activation, can be assigned to light zone (LZ), dark zone proliferation (DZp), or dark zone differentiation (DZd) states, as compartmentalized by the antagonistic molecular programs of selection, proliferation, and somatic hypermutation respectively. In the bone marrow, an epigenetic reader, BRWD1, orchestrates the sequential stages of B cell progenitor proliferation and B cell receptor recombination. Here, we analyze mice with a conditional knockout of Brwd1 in follicular B cells (Cd23Cre/wt;Brwd1fl/fl) and GC B cells (AicdaCre/wt;Brwd1fl/fl) to investigate the functions of BRWD1 during peripheral B cell activation. Compared to Brwd1fl/fl mice, Cd23Cre/wt;Brwd1fl/fl mice show diminished GC B cell responses and class switch recombination after immunization. By contrast, AicdaCre/wt;Brwd1fl/fl mice exhibit increased GC B cell proliferation but defects in affinity maturation and tolerance. Somatic hypermutation and differentiation into memory and plasma cells are intact. RNA-seq and ATAC-seq analyses of GC B cells from AicdaCre/wt;Brwd1fl/fl mice indicate that BRWD1 deficiency alters the transcriptional and epigenetic identities of the LZ, DZp, and DZd states. Our results thus demonstrate that BRWD1 regulates multiple transitions along B cell developmental and activation pathways, suggesting stringent epigenetic control of GC states drives positive and negative selection.
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BibTeX
@article{wright2026brwd1,
title = {{BRWD1 directs B cell epigenetic states required for germinal center initiation, maintenance and function.}},
author = {Nathaniel E Wright and Domenick E Kennedy and Junting Ai and Margaret L Veselits and Mary Attaway and Young Me Yoon and Madeleine S Durkee and Jacob Veselits and Mark Maienschein-Cline and Malay Mandal and Marcus R Clark},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77293-7},
url = {https://europepmc.org/article/MED/42864370},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - BRWD1 directs B cell epigenetic states required for germinal center initiation, maintenance and function.
AU - Nathaniel E Wright
AU - Domenick E Kennedy
AU - Junting Ai
AU - Margaret L Veselits
AU - Mary Attaway
AU - Young Me Yoon
AU - Madeleine S Durkee
AU - Jacob Veselits
AU - Mark Maienschein-Cline
AU - Malay Mandal
AU - Marcus R Clark
PY - 2026
DA - 2026/09/10
JO - Nature communications
DO - 10.1038/s41467-026-77293-7
UR - https://europepmc.org/article/MED/42864370
AB - Germinal center (GC) B cells, differentiated from follicular B cells following activation, can be assigned to light zone (LZ), dark zone proliferation (DZp), or dark zone differentiation (DZd) states, as compartmentalized by the antagonistic molecular programs of selection, proliferation, and somatic hypermutation respectively. In the bone marrow, an epigenetic reader, BRWD1, orchestrates the sequential stages of B cell progenitor proliferation and B cell receptor recombination. Here, we analyze mice with a conditional knockout of Brwd1 in follicular B cells (Cd23Cre/wt;Brwd1fl/fl) and GC B cells (AicdaCre/wt;Brwd1fl/fl) to investigate the functions of BRWD1 during peripheral B cell activation. Compared to Brwd1fl/fl mice, Cd23Cre/wt;Brwd1fl/fl mice show diminished GC B cell responses and class switch recombination after immunization. By contrast, AicdaCre/wt;Brwd1fl/fl mice exhibit increased GC B cell proliferation but defects in affinity maturation and tolerance. Somatic hypermutation and differentiation into memory and plasma cells are intact. RNA-seq and ATAC-seq analyses of GC B cells from AicdaCre/wt;Brwd1fl/fl mice indicate that BRWD1 deficiency alters the transcriptional and epigenetic identities of the LZ, DZp, and DZd states. Our results thus demonstrate that BRWD1 regulates multiple transitions along B cell developmental and activation pathways, suggesting stringent epigenetic control of GC states drives positive and negative selection.
SN - 2041-1723
ER -