Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ZBTB16
Cytogenetic location: 11q23.2 Genomic coordinates (GRCh38): 11:114,059,711-114,256,770 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.2 | Leukemia, acute promyelocytic, PL2F/RARA type | 3 |
Chen et al. (1993) identified the PLZF gene on chromosome 11 as the fusion partner of the retinoic acid receptor-alpha gene (RARA; 180240) on chromosome 17 in a Chinese patient with acute promyelocytic leukemia (APL; 612376) and a translocation t(11;17)(q23;21). Chen et al. (1993) described the PLZF gene.
Reid et al. (1995) showed that murine PLZF is expressed at highest levels in undifferentiated, multipotential hematopoietic progenitor cells and its expression declines as cells become more mature and committed to various hematopoietic lineages. In the human there is a lack of PLZF protein expression in mature peripheral blood mononuclear cells and high PLZF levels in the nuclei of CD34+ human bone marrow progenitor cells. Unlike many transcription factors, PLZF protein in these cells shows a distinct punctate distribution, suggesting its compartmentalization in the nucleus.
Zhang et al. (1999) identified at least 4 alternative splicings (AS-I, -II, -III, and -IV) within exon 1 of the PLZF gene. AS-I was detected in most tissues tested, whereas AS-II, -III, and -IV were present in the stomach, testis, and heart, respectively. Although splicing donor and acceptor signals at exon-intron boundaries for AS-I and exons 1-6 were classic (gt-ag), AS-II, -III, and -IV had atypical splicing sites. These alternative splicings, nevertheless, maintained the open reading frame and may encode isoforms with absence of important functional domains. In mRNA species without AS-I, there is a relatively long 5-prime UTR of 6.0 kb. Zhang et al. (1999) determined that PLZF is a well-conserved gene from C. elegans to human. PLZF paralogous sequences are found in the human genome. The presence of 2 MLL/PLZF-like alignments on human chromosomes 11q23 and 19 suggests a syntenic replication during evolution.
Using quantitative RT-PCR, Plaisier et al. (2012) found that ZBTB16 expression was highest in heart and skeletal muscle in both human and mouse. Within muscle, ZBTB16 expression was similar across fiber types.
Kang et al. (2003) found that endogenous PLZF in a human promyelocytic cell line was modified by conjugation with SUMO1 (601912) and that PLZF colocalized with SUMO1 in the nucleus of transfected human embryonic kidney cells. Site-directed mutagenesis identified lys242 in transcriptional repression domain-2 as the site of PLZF sumoylation. Reporter gene assays suggested that SUMO1 modification of lys242 was required for transcriptional repression by PLZF, and electrophoretic mobility shift assays showed sumoylation increased the DNA-binding activity of PLZF. PLZF-mediated regulation of the cell cycle and transcriptional repression of the cyclin A2 gene (CCNA2; 123835) were also dependent on sumoylation of PLZF on lys242.
Ikeda et al. (2005) found that PLZF was 1 of 24 genes upregulated during osteoblastic differentiation of cultured OPLL (602475) ligament cells. PLZF was highly expressed during osteoblastic differentiation in all ligament and mesenchymal stem cells examined. Silencing of the PLZF gene by small interfering RNA in human and mouse mesenchymal stem cells reduced expression of osteoblast-specific genes, such as alkaline phosphatase (ALPL; 171760), collagen 1A1 (COL1A1; 120150), Cbfa1 (RUNX2; 600211), and osteocalcin (BGLAP; 112260). PLZF expression was unaffected by the addition of BMP2 (112261), and BMP2 expression was not affected by PLZF expression. In a mouse mesenchymal cell line, overexpression of PLZF increased expression of Cbfa1 and Col1a1; on the other hand, CBFA1 overexpression did not affect expression of Plzf. Ikeda et al. (2005) concluded that PLZF plays a role in early osteoblastic differentiation and is an upstream regulator of CBFA1.
Using yeast 2-hybrid analysis and protein pull-down assays, Rho et al. (2006) showed that PLZF interacted with the CCS3 isoform of EEF1A1 (130590). Mutation analysis revealed that repressor domain-2 and the zinc finger domain of PLZF were required for the interaction. CCS3 was required for the transcriptional effects of PLZF in reporter gene assays.
Tissing et al. (2007) found that 8 hours of prednisolone treatment altered expression of 51 genes in leukemic cells from children with precursor-B- or T-acute lymphoblastic leukemia compared with nonexposed cells. The 3 most highly upregulated genes were FKBP5 (602623), ZBTB16, and TXNIP (606599), which were upregulated 35.4-, 8.8-, and 3.7-fold, respectively.
Using microarray analysis, Good and Tangye (2007) showed that naive splenic B cells expressed higher levels of transcription factors KLF4 (602253), KLF9 (602902), and PZLF compared with memory B cells. Activation of naive B cells through CD40 (109535) and B-cell receptor downregulated expression of these cellular quiescence-associated transcription factors. Overexpression of KLF4, KLF9, and PZLF in memory B cells delayed their entry into cell division and proliferation. Good and Tangye (2007) concluded that memory B cells undergo a rewiring process that results in a significantly reduced activation threshold compared with naive B cells, allowing them to enter division more quickly, to differentiate into Ig-secreting plasma cells, and to more rapidly produce antibodies.
Savage et al. (2008) used flow cytometric sorting of Cd1d (188410)-restricted cells to isolate mouse natural killer T (NKT) cells and found that Plzf was overexpressed in NKT cells compared with naive and activated T-cell subsets. RT-PCR also detected high expression of Ckrox (ZBTB7B; 607646) in NKT cells. Plzf-deficient NKT cells did not undergo full thymic maturation. Savage et al. (2008) concluded that PLZF is a transcriptional signature of NKT cells that directs their innate-like effector differentiation during thymic development.
Using a yeast 2-hybrid screen, Thirkettle et al. (2009) identified human PLZF as an interacting protein with human LYRIC (MTDH; 610323). Coexpression of the 2 proteins led to reduced PLZF-mediated repression by reducing PLZF promoter binding. The interaction occurred via both the N and C termini of LYRIC and a region C-terminal to the RD2 region of PLZF, which includes the first 2 zinc fingers and 2 sumoylated lys residues. Both proteins colocalized to nuclear bodies containing histone deacetylases, which promote PLZF-mediated repression. Thirkettle et al. (2009) proposed that cells with altered LYRIC expression evade apoptosis and increase cell growth during tumorigenesis through regulation of PLZF repression.
Using SNP mapping arrays to fine map genomic imbalances in primary malignant mesothelioma (156240)-derived cell lines, Cheung et al. (2010) identified deletions of multiple chromosomal segments, including 11q23, which encompassed PLZF. RT-PCR and immunoblot analyses revealed significant downregulation of PLZF in malignant mesothelioma cell lines. Ectopic expression of PLZF in PLZF-deficient malignant mesothelioma cells resulted in decreased cell viability and colony formation, as well as increased apoptosis. Cheung et al. (2010) concluded that PLZF deletion is common in malignant mesothelioma and that downregulation of PLZF may contribute to malignant mesothelioma pathogenesis by promoting cell survival.
Mathew et al. (2012) reported that PLZF is prominently associated with cullin-3 (CUL3; 603136) in natural killer T cell thymocytes.. PLZF transports CUL3 to the nucleus, where the 2 proteins are associated within a chromatin modifying complex. Furthermore, PLZF expression results in selective ubiquitination changes of several components of this complex. CUL3 was also found associated with the BTB-ZF transcription factor BCL6 (109565), which directs the germinal center B cell and follicular T-helper cell programs. Conditional CUL3 deletion in mice demonstrated an essential role for CUL3 in the development of PLZF- and BCL6-dependent lineages. Mathew et al. (2012) concluded that distinct lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the ubiquitination pattern of their associated chromatin-modifying complex. They proposed that this function is essential to direct the differentiation of several T- and B-cell effector programs, and may also be involved in the oncogenic role of PLZF and BCL6 in leukemias and lymphomas.
By microarray analysis, Plaisier et al. (2012) found that Zbtb16 exhibited robust induction in both brown adipose tissue and skeletal muscle during acute adaptive thermogenesis in mice. Quantitative PCR and Western blot analyses confirmed induction of Zbtb16 expression at the transcript and protein levels during adaptive thermogenesis in mice. Zbtb16 mRNA and protein expression increased during differentiation of mouse brown adipocytes. Overexpression of Zbtb16 in brown adipocytes induced components of the thermogenic program, including genes involved in fatty acid oxidation, glycolysis, and mitochondrial function. Zbtb16 overexpression also increased mitochondrial number, as well as respiratory capacity and uncoupling. The effects of Zbtb16 overexpression were accompanied by decreased triglyceride content and increased carbohydrate utilization in brown adipocytes. Natural variation in Zbtb16 mRNA levels in multiple tissues across a panel of mouse strains correlated inversely with body weight and fat content.
Using lineage tracing and transfer studies, Constantinides et al. (2014) identified and characterized a novel subset of lymphoid precursors in mouse fetal liver and adult bone marrow that transiently express high amounts of PLZF, a transcription factor associated with natural killer (NK) T cell development. PLZF-high cells were committed innate lymphoid cell (ILC) progenitors with multiple ILC1, ILC2, and ILC3 potential at the clonal level. They excluded classical lymphoid tissue inducers (LTis) and NK cells, but included a peculiar subset of NK1.1(+)DX5(-) 'NK-like' cells residing in the liver. Deletion of PLZF markedly altered the development of several ILC subsets, but not LTis or NK cells. PLZF-high precursors also expressed high amounts of ID2 (600386) and GATA3 (131320), as well as TOX (606863), a known regulator of PLZF-independent NK and LTi lineages. Constantinides et al. (2014) concluded that these results established novel lineage relationships between ILC, NK, and LTi cells, and identified the common precursor to ILCs, termed ILCP. The findings also revealed the broad, defining role of PLZF in the differentiation of innate lymphocytes.
By evaluating the transcriptome in cells with increasing expression of CCR6 (601835), a marker of Th17 cell (see 603149) differentiation, Singh et al. (2015) detected progressive upregulation of PLZF. Chromatin immunoprecipitation analysis for modified histones, p300 (EP300; 602700), and PLZF identified enhancer-like sites upstream of the transcription start site of CCR6 that bound PLZF in CCR6-positive cells. Knockdown of ZBTB16 downregulated expression of CCR6 and other Th17-associated genes. ZBTB16 and RORC (602943) cross-regulated each other, and PLZF bound to the RORC promoter in CCR6-positive cells. Singh et al. (2015) noted that Plzf was not expressed in mouse Th17 cells. They concluded that PLZF is an activator of transcription important both for Th17 differentiation and for maintenance of the Th17 phenotype in human cells.
PLZF/RARA Fusion Protein
Chen et al. (1994) cloned cDNAs encoding PLZF-RARA chimeric proteins and studied their transactivating activities. A 'dominant-negative' effect was observed when PLZF-RARA fusion proteins were cotransfected with vectors expressing RARA and retinoid X receptor alpha (RXRA; 180245). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicated the fusion proteins in the molecular pathogenesis of acute promyelocytic leukemia (APL; 612376).
Lin et al. (1998) reported that the association of PLZF-RAR-alpha and PML-RAR-alpha (see 102578) with the histone deacetylase complex (see 605164) helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of retinoic acid-sensitive, and restore retinoid responses of retinoic acid-resistant, APL cell lines. Lin et al. (1998) concluded that oncogenic retinoic acid receptors mediate leukemogenesis through aberrant chromatin acetylation, and that pharmacologic manipulation of nuclear receptor cofactors may be a useful approach in the treatment of human disease.
Grignani et al. (1998) demonstrated that both PML-RAR-alpha and PLZF-RAR-alpha fusion proteins recruit the nuclear corepressor (NCOR; see 600849)-histone deacetylase complex through the RAR-alpha CoR box. PLZF-RAR-alpha contains a second, retinoic acid-resistant binding site in the PLZF amino-terminal region. High doses of retinoic acid release histone deacetylase activity from PML-RAR-alpha, but not from PLZF-RAR-alpha. Mutation of the NCOR binding site abolishes the ability of PML-RAR-alpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biologic effects of PLZF-RAR-alpha from being an inhibitor to an activator of the retinoic acid signaling pathway. Therefore, Grignani et al. (1998) concluded that recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of retinoic acid on the stability of the PML-RAR-alpha and PLZF-RAR-alpha corepressor complexes determines the differential response of APLs to retinoic acid.
Guidez et al. (2007) identified CRABP1 (180230) as a target of both PLZF and the RARA/PLZF fusion protein. PLZF repressed CRABP1 through propagation of chromatin condensation from a remote intronic binding element, culminating in silencing of the CRABP1 promoter. Although the canonical PLZF/RARA oncoprotein had no effect on PLZF-mediated repression, the reciprocal translocation product, RARA/PLZF, bound to this remote binding site, recruited p300, and induced promoter hypomethylation and CRABP1 upregulation. Similarly, retinoic acid-resistant murine blasts that expressed both fusion proteins expressed much higher levels of Crabp1 than retinoic acid-sensitive cells expressing Plzf/Rara alone. RARA/PLZF conferred retinoic acid resistance to a retinoid-sensitive acute myeloid leukemia cell line in a CRABP1-dependent fashion. Guidez et al. (2007) concluded that upregulation of CRABP1 by RARA/PLZF contributes to retinoid resistance in leukemia.
Ahmad et al. (1998) reported the crystal structure of the BTB domain of PLZF. The BTB domain (also known as the POZ domain) is an evolutionarily conserved protein-protein interaction motif found at the N terminus of 5 to 10% of C2H2-type zinc finger transcription factors. The BTB domain has transcriptional repression activity and interacts with components of the histone deacetylase complex. The latter association provides a mechanism of linking the transcription factor with enzymatic activities that regulate chromatin conformation.
Zhang et al. (1999) sequenced a 201-kb genomic DNA region containing the entire PLZF gene. Repeated elements accounted for 19.83%, and no obvious coding information other than PLZF was present in this region. PLZF was found to contain 6 exons and 5 introns, and the exon organization corresponded well with protein domains. Zhang et al. (1999) identified at least 4 alternative splicings (AS-I, -II, -III, and -IV) within exon 1.
Van Schothorst et al. (1999) determined that the ZNF145 gene contains 7 exons and spans at least 120 kb. The untranslated exon 1 is located within a CpG island, and several SP1 (189906)- and GATA1 (305371)-binding sites are upstream of exon 1.
By FISH, Chen et al. (1993) localized the PLZF gene to chromosome 11q23.1.
Almost all patients with acute promyelocytic leukemia (APL; 612376) have a chromosomal translocation t(15;17)(q22;q21). Molecular studies reveal that the translocation results in a chimeric gene through fusion between the promyelocytic leukemia gene (PML; 102578) on chromosome 15 and the retinoic acid receptor-alpha gene (RARA; 180240) on chromosome 17. Chen et al. (1993) reported studies of a Chinese patient with APL and a variant translocation t(11;17)(q23;21) in which the PLZF gene on chromosome 11q23.1 was fused to the RARA gene on chromosome 17. Similar to t(15;17) APL, all-trans retinoic acid treatment produced an early leukocytosis which was followed by a myeloid maturation, but the patient died too early to achieve remission.
Zhang et al. (1999) characterized the chromosomal breakpoints and joining sites in the index acute promyelocytic leukemia case with t(11;17), reported by Chen et al. (1993). The results suggested the involvement of a DNA damage-repair mechanism.
Reclassified Variants
The M617V variant (176797.0001) identified by Fischer et al. (2008) has been reclassified as a variant of unknown significance. Fischer et al. (2008) had identified the M617V variant (176797.0001) in a patient with skeletal defects, genital hypoplasia, and impaired intellectual development (see 612447).
Cheng et al. (1999) generated transgenic mice with PLZF-RARA and NPM (164040)-RARA. PLZF-RARA transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage in life (within 3 months in 5 of 6 mice), whereas 3 NPM-RARA transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF-RARA transgenic mice, those from NPM-RARA transgenic mice could be induced to differentiate by all-trans-retinoic acid (ATRA). Cheng et al. (1999) found that in interacting with nuclear coreceptors the 2 fusion proteins had different ligand sensitivities, which may be the underlying molecular mechanism for differential responses to ATRA. These data clearly established the leukemogenic role of PLZF-RARA and NPM-RARA and the importance of fusion receptor/corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.
He et al. (2000) generated transgenic mice expressing RARA-PLZF and PLZF-RARA in their promyelocytes. RARA-PLZF transgenic mice did not develop leukemia. However, PLZF-RARA/RARA-PLZF double transgenic mice developed leukemia with classic APL features. The authors demonstrated that RARA-PLZF can interfere with PLZF transcriptional repression, and that this is critical for APL pathogenesis, since leukemias in PLZF-deficient/PLZF-RARA mutants and in PLZF-RARA/RARA-PLZF transgenic mice were indistinguishable. Thus, both products of a cancer-associated translocation are crucial in determining the distinctive features of the disease.
Barna et al. (2000) generated Zfp145 -/- mice and showed that Plzf is essential for patterning of the limb and axial skeleton. Inactivation of the gene resulted in patterning defects affecting all skeletal structures of the limb, including homeotic transformations of anterior skeletal elements into posterior structures. They demonstrated that Plzf acts as a growth-inhibitory and proapoptotic factor in the limb bud. The expression of members of the Abdominal B (Abdb) Hox gene complex (see 142956), as well as genes encoding bone morphogenetic proteins (e.g., 112267), was altered in the developing limb of the Zfp145 -/- mice. The mice also exhibited anterior-directed homeotic transformation throughout the axial skeleton with associated alterations in Hox gene expression. Plzf is, therefore, a mediator of anterior-to-posterior patterning in both the axial and appendicular skeleton and acts as a regulator of Hox gene expression.
Barna et al. (2002) determined that the defects in Plzf -/- mice were due to spatial, but not temporal, deregulation of the Abdb Hoxd complex. They identified several Plzf-binding sites in Hoxd11 (142986) and showed that Plzf bound Hoxd11 genomic DNA fragments as a dimer or possibly a trimer, mostly when DNA loops were formed. Barna et al. (2002) also found evidence of long-range interactions between distant Plzf-binding sites within the Hoxd regulatory elements. Plzf mediated transcriptional repression of a Hoxd reporter construct, and in the absence of Plzf, there were increased acetylated histones on Hoxd regulatory regions. Plzf showed dose-dependent transcriptional repression of a Hoxd reporter in mouse anterior limb micromass cultures, but there was no repression in posterior limb micromass cultures. Plzf also directly tethered the polycomb protein Bmi1 (164831) on DNA, which antagonized posteriorizing signals in the limb. Barna et al. (2002) concluded that recruitment of histone deacetylases and polycomb proteins by PLZF favors transition from euchromatin to heterochromatin.
Adult germline stem cells are capable of self-renewal, tissue regeneration, and production of large numbers of differentiated progeny. The mouse mutant 'luxoid' (lu) arose spontaneously and was mapped to mouse chromosome 9 (Green, 1955), and was initially characterized by its semidominant abnormalities and recessive skeletal and male infertility phenotypes (Forsthoefel, 1958). Buaas et al. (2004) showed that the mouse mutant luxoid affects adult germline stem cell self-renewal. Young homozygous luxoid mutant mice produce limited numbers of normal spermatozoa and then progressively lose their germline after birth. Transplantation studies showed that germ cells of mutant mice did not colonize recipient testes, suggesting that the defect is intrinsic to the stem cells. Buaas et al. (2004) determined that the luxoid mutant contains a nonsense mutation in the Plzf gene, a transcriptional repressor that regulates the epigenetic state of undifferentiated cells. They showed, furthermore, that Plzf is coexpressed with Oct4 (164177) in undifferentiated spermatogonia. This was said to be the first gene found to be required in germ cells for stem cell self-renewal in mammals.
Costoya et al. (2004) likewise showed that Plzf has a crucial role in spermatogenesis. Expression of the gene was restricted to gonocytes and undifferentiated spermatogonia and was absent in the tubules of W/W(v) mutants that lack these cells. Mice lacking Plzf underwent a progressive loss of spermatogonia with age, associated with increases in apoptosis and subsequent loss of tubule structure but without overt differentiation defects or loss of the supporting Sertoli cells. Spermatogonia transplantation experiments revealed a depletion of spermatogonia stem cells in the adult. These and other results identified Plzf as a spermatogonia-specific transcription factor in the testis that is required to regulate self-renewal and maintenance of the stem cell pool.
Barna et al. (2005) identified a genetic interaction between Gli3 (165240) and Plzf that is required specifically at very early stages of limb development for all proximal cartilage condensations in the hindlimb (femur, tibia, fibula). Notably, distal condensations comprising the foot were relatively unperturbed in Gli3/Plzf double knockout mouse embryos. Barna et al. (2005) demonstrated that the cooperative activity of Gli3 and Plzf establishes the correct temporal and spatial distribution of chondrocyte progenitors in the proximal limb bud independently of proximal-distal (P-D) patterning markers and overall limb bud size. Moreover, the limb defects in the double knockout embryos correlated with the transient death of a specific subset of proximal mesenchymal cells that express bone morphogenetic protein receptor type 1B (Bmpr1b; 603248) at the onset of limb development. Barna et al. (2005) concluded that development of proximal and distal skeletal elements is distinctly regulated during early limb bud formation. The initial division of the vertebrate limb into 2 distinct molecular domains is consistent with fossil evidence indicating that the upper and lower extremities of the limb have different evolutionary origins.
This variant, formerly titled SKELETAL DEFECTS, GENITAL HYPOPLASIA, AND IMPAIRED INTELLECTUAL DEVELOPMENT, has been reclassified because the pathogenicity of the variant has not been confirmed.
In a 12.75-year-old boy with skeletal defects, genital hypoplasia, and mental retardation (see 612447), originally reported by Wieczorek et al. (2002), Fischer et al. (2008) performed array-based CGH and identified an approximately 8-Mb de novo deletion on the paternal chromosome 11, a region containing about 72 genes. Sequence analysis of the candidate gene ZBTB16 on the maternal allele revealed a c.1849A-G transition in exon 6, resulting in a met617-to-val (M617V) substitution at a highly conserved residue within the eighth zinc finger motif of the PLZF protein, predicted to destabilize the alpha helix of the zinc finger that forms the contact with the DNA duplex. Reporter gene assays showed that the mutant PLZF decreased luciferase activity by only 10%, compared to an approximately 35% decrease with wildtype PLZF, suggesting that this represents a hypomorphic allele. The mutation was not found in 200 normal control alleles. No ZBTB16 mutation was found in 41 patients who had clinical overlap with this patient, including patients with severe hypoplasia of forearms.
Hamosh (2021) noted that the M617V variant was not present in the gnomAD database (January 4, 2021); however, the variant was identified by Fischer et al. (2008) by sequencing of ZBTB16 as a candidate in an 8-Mb interval of 72 genes that were deleted on the paternal allele. Although a mouse model of a knockout of Zbtb16 has skeletal abnormalities, and this missense variant was associated with reduced luciferase repression compared with the wildtype allele, absence of identification of other patients with a skeletal phenotype and variants in this gene as well as limited search for other possible causes in the proband suggest reclassification of this variant until additional evidence of the role of ZBTB16 in this phenotype is reported.
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