BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis. BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis

Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. We demonstrate in small pre-B cells, that the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 differentially regulated over 7000 genes including repressing proliferative and inducing differentiation programs. However, BRWD1 did not regulate expression of transcription factors required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations had 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. Overall design: 59 samples from mouse and human: 12 ATAC-seq samples from both mouse and human; 21 RNA-seq samples from human; 6 RNA-seq samples from mouse; 6 ChIP-seq samples from mouse, 2 input controls for the ChIP-seq samples from mouse. Mouse samples available in duplicate. Human samples are classified into one of three genotypic backgrounds, with varying number per group.