BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis
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PROVIDER: PRJNA400057 | ENA |
REPOSITORIES: ENA
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Project description: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.
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Project description:Pax5 controls the identity and development of B cells by repressing lineage-inappropriate genes and activating B-cell-specific genes. Here, we used genome-wide approaches to identify Pax5 target genes in pro-B and mature B cells. In these cell types, Pax5 bound to 40% of the cis- regulatory elements defined by mapping Dnase I hypersensitive (DHS) sites, transcription start sites and histone modifications. Although Pax5 bound to 8,000 target genes, it regulated only 4% of them in pro-B and mature B cells by inducing enhancers at activated genes and eliminating DHS sites at repressed genes. Pax5-regulated genes in pro-B cells account for 23% of all expression changes occurring between common lymphoid progenitors and committed pro-B cells, which identifies Pax5 as an important regulator of this developmental transition. Regulated Pax5 target genes minimally overlap in pro-B and mature B cells, which reflects massive expression changes between these cell types. Hence, Pax5 controls B cell identity and function by regulating distinct target genes in early and late B lymphopoiesis. 44 samples (16 RNA-seq, 15 ChIP-seq, 6 DHS-seq, 5 Bio-ChIP-seq, 2 CAGE-seq). All but four samples in in 2 biological replicates (8819, 8275, 8095, 8666). WT and experimental samples are provided.
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