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Genes Dev. 2018 Jan 15;32(2):96-111. doi: 10.1101/gad.309583.117. Epub 2018 Feb 9.

Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming.

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Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
International Max Planck Research School for Molecular and Cellular Biology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center, 69120 Heidelberg, Germany.
Department of Medicine, Division of Medial Genetics, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA.


B-cell fate determination requires the action of transcription factors that operate in a regulatory network to activate B-lineage genes and repress lineage-inappropriate genes. However, the dynamics and hierarchy of events in B-cell programming remain obscure. To uncouple the dynamics of transcription factor expression from functional consequences, we generated induction systems in developmentally arrested Ebf1-/- pre-pro-B cells to allow precise experimental control of EBF1 expression in the genomic context of progenitor cells. Consistent with the described role of EBF1 as a pioneer transcription factor, we show in a time-resolved analysis that EBF1 occupancy coincides with EBF1 expression and precedes the formation of chromatin accessibility. We observed dynamic patterns of EBF1 target gene expression and sequential up-regulation of transcription factors that expand the regulatory network at the pro-B-cell stage. A continuous EBF1 function was found to be required for Cd79a promoter activity and for the maintenance of an accessible chromatin domain that is permissive for binding of other transcription factors. Notably, transient EBF1 occupancy was detected at lineage-inappropriate genes prior to their silencing in pro-B cells. Thus, persistent and transient functions of EBF1 allow for an ordered sequence of epigenetic and transcriptional events in B-cell programming.


B-cell programming; DNA methylation; EBF1; IRF4; Pax5; chromatin

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