Transcriptional and epigenetic regulation of B cell development

Abstract

B cell development starts in the bone marrow where hematopoietic stem cells (HSCs) progress through sequential developmental stages, as it differentiates into a naïve B cell expressing surface immunoglobulin. In the periphery, B cells that encounter antigen can further differentiate into antibody-secreting plasma cells. In this review, we focus on two factors, E47 and ELL2, which play important roles in the regulation of B cell development in the bone marrow and differentiation of mature B cells into plasma cells in the periphery, respectively. First, E47 activity is required for B cell development in the bone marrow. In addition, we have identified a cell-intrinsic role for E47 in regulating efficient self-renewal and long-term multilineage bone marrow reconstitution potential of HSCs. Second, we explored the role of transcription elongation factors in the super elongation complex (SEC), including ELL2 (eleven-nineteen lysine-rich leukemia factor) in driving poly(A) site choice and plasma cell development. We found that elongation factors impel high levels of IgH mRNA production and alternative processing at the promoter proximal, secretory-specific (sec) poly(A) site in plasma cells by enhancing RNA polymerase II modifications and downstream events. The sec poly(A) site, essentially hidden in B cells, is found by SEC factors in plasma cells.

Cross Talk between Immunoglobulin Heavy-Chain Transcription and RNA Surveillance during B Cell Development

“…It was reported previously that the rate of RNAPII elongation shows some increase in plasma cells (45). We indeed observed a boost of the IgH transcription level and a low level of NMUP in plasma cells compared to B cells (Fig.…”

“…Previous studies have documented that IgH transcription rates are increased after LPS stimulation and in terminally differentiated plasma cells (16,45). To confirm these findings, we determined pre-mRNA levels of functional IgH alleles that are PTC free and therefore not sensitive to NMUP.…”

A novel virus-inducible enhancer of the interferon-β gene with tightly linked promoter and enhancer activities

“…The predicted E47, NFAT and CEBP sites were highly conserved between human and mouse sequences. Both NFAT and C/EBPβ play key roles in innate immune activity (57,58), and E47 has well-documented roles in B cell development (59). However, we found no report of any of these factors directly regulating Type-I interferon expression, and no predicted binding sites for either NFκB or the IRF-family of transcription factors, both of which are known to regulate IFNB1 transcription (28).…”

Immunoglobulin kappa variable region gene selection during early human B cell development in health and systemic lupus erythematosus

“…Successful expression of the pre-B cell receptor excludes recombination events on the second IGH allele and also activates enhancers that initiate rearrangement of the IGK locus. If functional rearrangement is not achieved on either allele at the IGK locus, then IGK is inactivated by deletional rearrangement with kappa deleting element (KDE) and gene rearrangement proceeds at the IGL locus (Hardy and Hayakawa, 2001;Santos et al, 2011).…”