Abstract

Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 regulates over 7000 genes to repress proliferative and induce differentiation programs. However, BRWD1 does not regulate the expression of TFs required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations have B-cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1-/- mice. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B-cell development.

Details

Title
BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis
Author
Mandal, Malay 1   VIAFID ORCID Logo  ; Maienschein-Cline, Mark 2 ; Maffucci, Patrick 3   VIAFID ORCID Logo  ; Veselits, Margaret 1 ; Kennedy, Domenick E 1   VIAFID ORCID Logo  ; McLean, Kaitlin C 1 ; Okoreeh, Michael K 1 ; Karki, Sophiya 4 ; Cunningham-Rundles, Charlotte 3 ; Clark, Marcus R 1 

1  Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA 
2  Core for Research Informatics, University of Illinois at Chicago, Chicago, Illinois, USA 
3  Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
4  Department of Research Biology, Genentech, South San Francisco, California, USA 
Pages
1-15
Publication year
2018
Publication date
Sep 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-06165-6
ProQuest document ID
2111724540
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.