Regulatory events in early and late B-cell differentiation.
We are studying transcriptional control of critical developmental decision points in B lymphocytes. Commitment to the B-lymphocyte lineage is dependent on the transcriptional regulator Pax5 and committed B lymphocytes represent the first developmental stage when V(H)-to-DJ recombination occurs in the immunoglobulin (Ig) heavy chain locus. We summarize our recent studies showing that methylation of histone H3 lysine 9, a heterochromatic chromatin modification, is present in the Ig V(H) region in hematopoietic progenitors and in non-B lineage hematopoietic cells. Pax5 is both necessary and sufficient to remove this heterochromatic mark in B cells. Using genetically altered mice, we have shown that terminal differentiation of B cells to memory and Ig-secreting plasma cells depends on the transcriptional repressor Blimp-1. Recent studies demonstrating a requirement for Blimp-1 in the formation of pre-plasma memory B cells, Ig-secreting plasma cells as well as preliminary data suggesting a requirement for Blimp-1 in the maintenance of long-lived plasma cells are summarized. We also summarize our recent studies on the regulation of Blimp-1, showing direct repression by Bcl-6 and providing evidence for activation by NF-kappaB following toll-like receptor signaling.
Johnson
Kristen
K
Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Shapiro-Shelef
Miriam
M
Tunyaplin
Chainarong
C
Calame
Kathryn
K
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000276:immunology; D006801:Humans; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D051757:PAX5 Transcription Factor; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology
D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1