From hematopoietic progenitors to B cells: mechanisms of lineage restriction and commitment

Abstract

The generation of B lymphocytes from hematopoietic progenitors requires lineage-specific transcription factors that progressively direct cell fate choices. Differentiation of hematopoietic stem cells to lymphoid progenitors requires Ikaros-dependent lineage priming and graded levels of PU.1, which are controlled by Ikaros and Gfi1. E2A drives expression of EBF1, which initiates B lineage specification. EBF1, in addition to Pax5, is necessary for commitment to the B cell lineage. As a model of gene activation in early B lymphopoiesis, mb-1 genes are activated sequentially by factors (e.g. EBF1) that initiate chromatin modifications before transcription. This review highlights the requisite interplay between transcription factors and epigenetic mechanisms in the context of B cell development.

Figure 1

Transcription factor expression during B lymphopoiesis. The progression of cells from hematopoietic stem cells through stages of B lymphopoiesis is shown. Shaded bars represent the levels of gene expression of transcription factors that are important in B cell development during the course of differentiation. HSCs (hematopoietic stem cells), MPPs (multipotent progenitors), LMPPs (lymphoid-primed MPPs), ELPs (early lymphoid progenitors), CLPs (common lymphoid progenitors), ETPs (early T lineage progenitors). Darker shading indicates increased gene expression. Important branch points during B lymphopoiesis are shown with arrows indicating alternative developmental pathways. Expression profiles were compiled using data from RefDIC (Reference Database of Immune Cells) http://refdic.rcai.riken.jp/profile.cgi and citations in the text.

Figure 2

Model of epigenetic regulation of the mb-1 promoter. Sequential steps involved in mb-1 transcriptional activation are shown. Association of chromatin remodeling complexes with promoter elements is indicated by shaded regions representing hypothesized Mi-2/NuRD and SWI/SNF occupancy. We propose that Mi-2/NuRD complexes are required to maintain hypermethylated, transcriptionally silent mb-1 promoters (top). The mb-1 promoter is primed for expression prior to transcriptional activation (middle). Priming following DNA binding of EBF, E2A and Runx1/CBFβ involves demethylation of CpGs at distal sites and chromatin remodeling following recruitment (by EBF1) of SWI/SNF. Efficient transcriptional activation of the mb-1 gene (bottom) requires 5' to 3' propagation of DNA demethylation, which allows appropriate binding of Pax5, Ets and Sp1, displacement of Mi-2/NuRD, and further modifications of chromatin by SWI/SNF.