Alternative titles; symbolsB LYMPHOCYTE-INDUCED MATURATION PROTEIN 1; BLIMP1POSITIVE REGULATORY DOMAIN I-BINDING FACTOR 1; PRDIBF1HGNC Approved Gene Symbol: PRDM...
Alternative titles; symbols
HGNC Approved Gene Symbol: PRDM1
Cytogenetic location: 6q21 Genomic coordinates (GRCh38): 6:106,046,728-106,109,937 (from NCBI)
PRDM1 is a DNA-binding transcriptional repressor. It exerts its repressive functions through recruitment of histone-modifying enzymes (e.g., HDAC2; 605164) and Groucho corepressors (see 600189) (summary by Smith et al., 2010).
▼ Cloning and Expression
The DNA sequences that are required for the transient induction of the beta-interferon gene (IFNB1; 147640) by virus are located within the beta-interferon promoter in a region containing both positive and negative regulatory sequences, including an element designated the 'positive regulatory domain I' (PRDI). By screening a human cDNA expression library with a probe containing multiple PRDI sites, Keller and Maniatis (1991) isolated a cDNA encoding a novel repressor of human beta-interferon gene expression, which they designated PRDIBF1. The deduced 789-amino acid PRDIBF1 protein has a predicted molecular mass of 88 kD and contains 5 zinc fingers of the TFIIA (600520) type near the C terminus. Northern blot analysis detected 5.7- and 3.5-kb PRDIBF1 messages in a human osteosarcoma cell line.
Huang (1994) determined that PRDIBF1 is the human homolog of the mouse Blimp1 gene, the expression of which drives the terminal differentiation of B lymphocytes. The author also identified a novel stretch of 100 amino acids, which he named the PR domain, that is conserved between PRDIBF1 and RIZ (601196).
Vincent et al. (2014) found that mouse Prdm1 was expressed in the second heart field from the early cardiac crescent stage to later stages when the heart tube had formed and second heart field mesoderm in the posterior pharyngeal arch was contributing to formation of the pharyngeal arch arteries. Prdm1 was also expressed in ectoderm and endoderm in the region where branchial arches were forming.
▼ Gene Function
Keller and Maniatis (1991) demonstrated that transcription of the PRDIBF1 gene increased upon virus induction. They showed that PRDIBF1 bound specifically to the PRDI element in the IFNB1 promoter and repressed PRDI-dependent transcription; repression was highly dependent on the location of the PRDI site.
Chang et al. (2000) found that BLIMP1 mRNA was present in both monocytes and granulocytes of healthy donors. Using immunocytochemistry on the monocytoid U937 and the pluripotential HL60 cell lines, Chang et al. (2000) demonstrated that BLIMP1 expression correlates with macrophage differentiation (i.e., adherence and expression of the macrophage-specific surface antigens CD11B (ITGAM; 120980) and CD11C (ITGAX; 151510)) of these cell lines. Likewise, induction of HL60 differentiation into granulocytes was also accompanied by BLIMP1 expression. During macrophage differentiation, riboprobe analysis indicated that MYC (190080) expression decreases, possibly explaining the cessation of division. Flow cytometry analysis revealed that blocking BLIMP1 expression delays or inhibits macrophage differentiation, CD11 expression, and the ability to phagocytose opsonized bacteria.
Using histochemical, immunofluorescence microscopy, and flow cytometric analyses, Angelin-Duclos et al. (2000) determined that BLIMP1 is expressed in plasma cells, but not memory B lymphocytes, of mouse and human primary and secondary lymphoid organs after immunization with T cell-independent or -dependent antigens. In mice, Blimp1 is also expressed in nonapoptotic, occasionally proliferating, CD10 (120520)- and peanut agglutinin-positive germinal center (GC) cells with a phenotype intermediate between B cells and plasma cells up to 12 days after immunization before disappearing. Most also express the plasma cell marker CD138 (SDC1; 186355), as well as IRF4 (601900) and cytoplasmic Ig, but not BCL6 (109565). Angelin-Duclos et al. (2000) concluded that BLIMP1 expression is critical for commitment to a plasma cell fate rather than a memory cell fate.
By FISH, Southern blot, and sequence analyses, Pasqualucci et al. (2006) found that 24% of activated B cell-like diffuse large cell lymphomas (DLBCLs), but no GC or unclassified DLBCLs, had an inactivated BLIMP1 gene in both alleles. Most non-GC DLBCLs lacked BLIMP1 protein expression, although BLIMP1 mRNA expression was present. Pasqualucci et al. (2006) concluded that BLIMP1 acts as a tumor suppressor gene whose inactivation contributes to lymphomagenesis by blocking differentiation of post-GC B cells into plasma cells.
Epidermal lineage commitment occurs when multipotent stem cells are specified into 3 lineages: the epidermis, the hair follicle, and the sebaceous gland. Using cell culture studies and genetic lineage tracing, Horsley et al. (2006) found that mouse stem cells expressing Blimp1 were upstream from other cells of the sebaceous gland lineage. Loss of Blimp1 through conditional gene targeting resulted in larger sebaceous glands, with enhanced pools of both slow-cycling progenitors and proliferative cells, accompanied by increased Myc expression. BrdU labeling experiments demonstrated that sebaceous gland defects associated with loss of Blimp1 led to enhanced bulge stem cell activity. Horsley et al. (2006) concluded the BLIMP1-expressing cells of the sebaceous gland are unipotent progenitors that control gland homeostasis and govern the activity of bulge stem cells.
Early specification of endomesodermal territories in the sea urchin embryo depends on a moving torus of regulatory gene expression. Smith et al. (2007) showed how this dynamic patterning function is encoded in a gene regulatory network subcircuit that includes the Otx (600036), Wnt8 (606360), and Blimp1 genes, the cis-regulatory controls systems of which had all been experimentally defined. A cis-regulatory reconstruction experiment revealed that Blimp1 autorepression accounts for progressive extinction of expression in the center of the torus, whereas its outward expansion follows reception of the Wnt8 ligand by adjacent cells. Smith et al. (2007) concluded that gene regulatory network circuitry controls not only static spatial assignment in development but also dynamic regulatory patterning.
PRDM1 represses the PAX5 gene (167414), which encodes a protein required for B-cell identity and survival. Mora-Lopez et al. (2007) identified a conserved PAX5-binding element within exon 1 of the human PRDM1 gene. Chromatin immunoprecipitation assays confirmed binding of PAX5 to this element, and PAX5 binding repressed PRDM1 activity in a reporter assay. Mora-Lopez et al. (2007) concluded that PAX5 negatively regulates PRDM1 expression in an autoregulatory negative feedback loop.
Using immunohistochemistry on mouse and human epidermis, Magnusdottir et al. (2007) demonstrated nuclear BLIMP1 expression in the granular layer, the inner root sheath, and companion layer of hair follicles and in mature sebocytes. Days after birth, mice with epidermis-specific conditional knockout of Blimp1 (CKO mice) developed abnormally wrinkled and scaly skin with delayed hair emergence. Establishment of normal appearance in CKO mice was followed by incessant scratching, leading to ulceration, hair loss, and scarring accompanied by splenomegaly and enlarged lymph nodes. The cornified layer of CKO neonates was compacted and lacked the normal 'basket weave' appearance, and this compaction persisted into adult life, where hyperkeratinization was evident. Immunofluorescence and electron microscopy showed impeded progression of granular layer cells into corneocytes in CKO mice, resulting in delayed formation of the epidermal permeability barrier. Gene expression analysis showed that Blimp1 regulated expression of multiple genes involved in late keratinocyte differentiation in the epidermis, including Blimp1 itself, the osmoregulator Nfat5 (604708), Fos (164810), and Dusp16 (607175). Magnusdottir et al. (2007) concluded that BLIMP1 is an important factor in transcriptional regulation in the epidermis and in control of water homeostasis during normal cornification.
Johnston et al. (2009) found that expression of the transcription factor Bcl6 (109565) in CD4+ T cells is both necessary and sufficient for in vivo T follicular helper (T(FH)) cell differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp1, an antagonist of Bcl6, inhibits T(FH) differentiation and help, thereby preventing B cell germinal center and antibody responses. Johnston et al. (2009) concluded that T(FH) cells are required for proper B cell responses in vivo and that Bcl6 and Blimp1 play central but opposing roles in T(FH) differentiation.
Using microarray, Western blot, RT-PCR, chromatin immunoprecipitation, and functional analyses, Smith et al. (2010) demonstrated that 3 distinct PRDM1 isoforms were induced in human CD56 (NCAM1; 116930)-dim natural killer (NK) cells in response to activation. PRDM1 coordinately suppressed IFNG (147570), TNF (191160), and TNFB (LTA; 153440) by binding to multiple conserved regulatory regions. Ablation of PRDM1 expression led to enhanced IFNG and TNF production without altering cytotoxicity. PRDM1 overexpression blocked cytokine production. Smith et al. (2010) identified PRDM1 response elements in the TNF and IFNG genes. Smith et al. (2010) concluded that PRDM1 is involved in negative regulation of NK cells in the innate immune response, as well as in regulation of B and T cells involved in adaptive immune responses.
By flow cytometric and RT-PCR analyses, Kallies et al. (2011) demonstrated that BLIMP1 was expressed in mouse and human NK lymphocytes and that it was upregulated during their maturation in an IL15 (600554)-dependent manner, with further upregulation mediated by IL12 (see 161560) and IL21 (605384). Mice lacking Rag2 (179616), and thus B and T cells, as well as Blimp1 expressed most NK-cell effector functions and were superior in their ability to control tumor cells in vivo, but granzyme B (GZMB; 123910) expression was significantly reduced and NK-cell proliferative potential was enhanced. Expression of Blimp1 and maturation of NK cells, unlike B and T cells, was not affected by the absence of Irf4 or Bcl6. However, Blimp1 expression required Tbet (TBX21; 604895). Kallies et al. (2011) concluded that the NK-cell gene regulatory network is distinct from that of other lymphocytes.
By flow cytometric analysis, Cretney et al. (2011) demonstrated that Blimp1 was expressed in a subset of mouse regulatory T cells (Tregs) that localized mainly to mucosal sites and expressed Il10 (124092) in a Blimp1-dependent manner. Blimp1 was also required for tissue homeostasis. Irf4, but not Tbet, was essential for Blimp1 expression and for differentiation of all effector Tregs. Cretney et al. (2011) concluded that the differentiation pathway that leads to the acquisition of Treg effector functions requires both IRF4 and BLIMP1.
Nakaki et al. (2013) showed that, without cytokines, simultaneous overexpression of 3 transcription factors, BLIMP1, PRDM14 (611781), and TFAP2C (601602), directs epiblast-like cells, but not embryonic stem cells, swiftly and efficiently into a primordial germ cell state. Notably, PRDM14 alone, but not BLIMP1 or TFAP2C, suffices for the induction of the primordial germ cell state in epiblast-like cells. The transcription factor-induced primordial germ cell state, irrespective of the transcription factors used, reconstitutes key transcriptome and epigenetic reprogramming in primordial germ cells, but bypasses a mesodermal program that accompanies primordial germ cell or primordial germ cell-like-cell specification by cytokines, including bone morphogenetic protein-4 (BMP4; 112262). Notably, the transcription factor-induced primordial germ cell-like cells contribute to spermatogenesis and fertile offspring.
Mackay et al. (2016) demonstrated that Hobit (616775) is specifically unregulated in tissue-resident memory T cells, and together with related Blimp1 mediates the development of these cells in skin, gut, liver, and kidney in mice. The Hobit-Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes, including natural killer T cells and liver-resident NK cells, all of which share a common transcriptional program. Hobit and Blimp1 are the central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.
Using RNA and protein expression profiling at single-cell resolution in mouse cells, Chihara et al. (2018) identified a module of coinhibitory receptors that includes not only several known coinhibitory receptors but many novel surface receptors. Chihara et al. (2018) functionally validated 2 novel coinhibitory receptors, activated protein C receptor (PROCR; 600646) and podoplanin (PDPN; 608863). The module of coinhibitory receptors is coexpressed in both CD4+ and CD8+ T cells and is part of a larger coinhibitory gene program that is shared by nonresponsive T cells in several physiologic contexts and is driven by the immunoregulatory cytokine IL27 (608273). Computational analysis identified the transcription factors PRDM1 and c-MAF (177075) as cooperative regulators of the coinhibitory module, and this was validated experimentally. This molecular circuit underlies the coexpression of coinhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumor immunity.
In mice, Vasanthakumar et al. (2020) found pronounced sexual dimorphism in Treg cells in visceral adipose tissue (VAT). Male VAT was enriched for Treg cells compared with female VAT, and Treg cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape, and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of Treg cells via the CCL2 (158105)-CCR2 (601267) axis. Androgen regulated the differentiation of a unique IL33 (608678)-producing stromal cell population specific to the male VAT, which paralleled the local expansion of Treg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident Treg cells in a BLIMP1 transcription factor-dependent manner. Vasanthakumar et al. (2020) concluded that sex-specific differences in Treg cells from VAT are determined by the tissue niche in a sex hormone-dependent manner to limit adipose tissue inflammation.
Using YAC mapping and somatic cell hybrid analysis, Mock et al. (1996) localized the human BLIMP1 gene to 6q21-q22.1, a region commonly deleted in B-cell non-Hodgkin lymphomas. By interspecific backcross analysis, they mapped the mouse Blimp1 gene to chromosome 10, 14 cM distal to the Myb locus (see 189990).
▼ Animal Model
Vertebrate skeletal muscles comprise distinct fiber types that differ in their morphology, contractile function, mitochondrial content, and metabolic properties. The transcriptional coactivator PGC1-alpha (PGC1A; 604517) is a key mediator of the physiologic stimuli that modulate fiber-type plasticity in postembryonic development (Lin et al., 2002). Myoblasts become fated to differentiate into distinct kinds of fibers early in development. Baxendale et al. (2004) presented data that provided molecular insight into the mechanism by which a specific group of muscle precursors is driven along a distinct pathway of fiber-type differentiation in response to positional cues in the vertebrate embryo. They showed that the gene u-boot (ubo), a mutation in which disrupts the induction of embryonic slow-twitch fibers (Roy et al., 2001), encodes the zebrafish homolog of Blimp1, a SET domain-containing transcription factor that promotes the terminal differentiation of B lymphocytes in mammals. Expression of ubo is induced by hedgehog (Hh) signaling in prospective slow muscle precursors, and its activity alone is sufficient to direct slow-twitch fiber-specific development by naive myoblasts. Brent and Tabin (2004) discussed this in relation to 'white meat or dark?' and the question of how slow (dark) and fast (white) muscle is established during embryogenesis.
Ohinata et al. (2005) demonstrated that Blimp1 has a critical role in the foundation of the mouse germ cell lineage, as its disruption causes a block early in the process of primordial germ cell formation. Blimp1-deficient mutant embryos formed a tight cluster of about 20 primordial germ cell-like cells, which failed to show the characteristic migration, proliferation, and consistent repression of homeobox genes that normally accompany specification of primordial germ cells. Using genetic lineage-tracing experiments, Ohinata et al. (2005) demonstrated that Blimp1-positive cells originating from the proximal posterior epiblast cells are indeed the lineage-restricted primordial germ cell precursors.
Kallies et al. (2006) found that Rag1 (179615) -/- mice reconstituted with fetal liver cells expressing a mutant Blimp1 lacking the DNA-binding domain developed a lethal multiorgan inflammatory disease caused by accumulation of effector and memory T cells. They concluded that BLIMP1 is an essential regulator of T-cell homeostasis and may regulate both B-cell and T-cell differentiation.
Martins et al. (2006) showed that Blimp1 -/- mouse thymocytes had decreased survival, and Blimp1 -/- mice had more peripheral effector T cells. Blimp1 -/- mice developed severe colitis, and Blimp1 -/- regulatory T cells were defective in blocking development of colitis. Compared with wildtype Cd4 (186940)-positive T cells, Blimp1 -/- Cd4-positive T cells proliferated more and produced more Il2 (147680) and Ifng (147570), but less Il10, after stimulation. Martins et al. (2006) concluded that BLIMP1 has a crucial function in controlling T-cell homeostasis and activation.
By targeting Prdm1 knockout to mouse cardiac progenitors in the primitive streak and thereafter in the second heart field, Vincent et al. (2014) found that Prdm1 was required for normal formation of the early outflow tract. Conditional Prdm1 mutant mice showed lateral arterial pole defects, such as transposition of the great arteries and partial loss of pharyngeal arch arteries derived from the fourth and sixth branchial arches. These defects were associated with reduced proliferation of progenitor cells in the second heart field. Conditional Prdm1 knockout did not result in neural crest dysfunction. Overexpression of a dominant-negative Prdm1 mutant resulted in a reduced outflow tract and a hypoplastic right ventricle.