Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch.

Two transcription factors, Pax5 and Blimp-1, form a gene regulatory network (GRN) with a double-negative loop, which defines either B-cell (Pax5 high) or plasma cell (Blimp-1 high) status as a binary switch. However, it is unclear how this B-cell GRN registers class switch DNA recombination (CSR), an event that takes place before the terminal differentiation to plasma cells. In the absence of Bach2 encoding a transcription factor required for CSR, mouse splenic B cells more frequently and rapidly expressed Blimp-1 and differentiated to IgM plasma cells as compared with wild-type cells.

Blimp1-mediated repression of negative regulators is required for osteoclast differentiation.

Regulation of irreversible cell lineage commitment depends on a delicate balance between positive and negative regulators, which comprise a sophisticated network of transcription factors. Receptor activator of NF-kappaB ligand (RANKL) stimulates the differentiation of bone-resorbing osteoclasts through the induction of nuclear factor of activated T cells c1 (NFATc1), the essential transcription factor for osteoclastogenesis. Osteoclast-specific robust induction of NFATc1 is achieved through an autoamplification mechanism, in which NFATc1 is constantly activated by calcium signaling while the negative regulators of NFATc1 are suppressed.

Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors.

Interleukin-21 (IL-21) is a pleiotropic cytokine that induces expression of transcription factor BLIMP1 (encoded by Prdm1), which regulates plasma cell differentiation and T cell homeostasis. We identified an IL-21 response element downstream of Prdm1 that binds the transcription factors STAT3 and IRF4, which are required for optimal Prdm1 expression. Genome-wide ChIP-Seq mapping of STAT3- and IRF4-binding sites showed that most regions with IL-21-induced STAT3 binding also bound IRF4 in vivo and furthermore revealed that the noncanonical TTCnnnTAA GAS motif critical in Prdm1 was broadly used for STAT3 binding.

Blimp-1/Prdm1 alternative promoter usage during mouse development and plasma cell differentiation.

The zinc-finger PR domain transcriptional repressor Blimp-1/Prdm1 plays essential roles in primordial germ cell specification, placental, heart, and forelimb development, plasma cell differentiation, and T-cell homeostasis. The present experiments demonstrate that the mouse Prdm1 gene has three alternative promoter regions. All three alternative first exons splice directly to exon 3, containing the translational start codon.