Alternative splicing regulates Prdm1/Blimp-1 DNA binding activities and co-repressor interactions

Prdm1/Blimp-1 is a master regulator of gene expression in diverse tissues of the developing embryo and adult organism. Its C-terminal zinc finger domain mediates nuclear import, DNA binding, and recruitment of the corepressors G9a and HDAC1/2. Alternatively spliced transcripts lacking exon 7 sequences encode a structurally divergent isoform (Blimp-1exon7) predicted to have distinct functions. Here we demonstrate that the short Blimp-1exon7 isoform lacks DNA binding activity and fails to bind G9a or HDAC1/2 but retains the ability to interact with PRMT5. To investigate functional roles of alternative splicing in vivo, we engineered novel mouse strains via embryonic stem (ES) cell technology. Like null mutants, embryos carrying a targeted deletion of exon 7 and exclusively expressing Blimp-1exon7 die at around embryonic day 10.5 (E10.5) due to placental defects. In heterozygousexon7mice, there is no evidence of dominant-negative effects. Mice carrying a knock-in allele with an exon 6-exon 7 fusion express full-length Blimp-1 only, develop normally, are healthy and fertile as adults, and efficiently generate ma-ture plasma cells. These findings strongly suggest that the short Blimp-1exon7 isoform is dispensable. We propose that devel-opmentally regulated alternative splicing is influenced by chromatin structure at the locus and fine-tunes Blimp-1’s functional capabilities. Originally cloned as a silencer of beta interferon gene expression(34) and subsequently identified as a master regulator of plasma cell terminal differentiation (68, 82), the zinc finger tran-scriptional repressor Prdm1/Blimp-1 governs a rapidly expanding repertoire of developmental processes (3). In the early embryo, Blimp-1 acts downstream of BMP/Smad signals to silence the de-fault somatic pathway and specify primordial germ cells (58, 83). At later stages, Blimp-1 regulates development of the placenta, posterior forelimb, pharyngeal arches, secondary heart field, and sensory vibrissae (64). Blimp-1 has essential roles in adult tissue homeostasis. Besides plasma cells, Blimp-1 also controls gene ex