BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis

Malay Mandal (), Mark Maienschein-Cline, Patrick Maffucci, Margaret Veselits, Domenick E. Kennedy, Kaitlin C. McLean, Michael K. Okoreeh, Sophiya Karki, Charlotte Cunningham-Rundles and Marcus R. Clark ()
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Malay Mandal: University of Chicago
Mark Maienschein-Cline: University of Illinois at Chicago
Patrick Maffucci: Icahn School of Medicine at Mount Sinai
Margaret Veselits: University of Chicago
Domenick E. Kennedy: University of Chicago
Kaitlin C. McLean: University of Chicago
Michael K. Okoreeh: University of Chicago
Sophiya Karki: Department of Research Biology, Genentech, South San Francisco
Charlotte Cunningham-Rundles: Icahn School of Medicine at Mount Sinai
Marcus R. Clark: University of Chicago

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06165-6

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