Journal articles: 'ZNF318'

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Nizhnichenko, Vladimir A., Alexey V. Boyko, Talia T. Ginanova, and Igor Yu Dolmatov. "Muscle Regeneration in Holothurians without the Upregulation of Muscle Genes." International Journal of Molecular Sciences 23, no. 24 (December 16, 2022): 16037. http://dx.doi.org/10.3390/ijms232416037.

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The holothurian Eupentacta fraudatrix is capable of fully restoring its muscles after transverse dissection. Although the regeneration of these structures is well studied at the cellular level, the molecular basis of the process remains poorly understood. To identify genes that may be involved in the regulation of muscle regeneration, the transcriptome of the longitudinal muscle band of E. fraudatrix has been sequenced at different time periods post-injury. An analysis of the map of biological processes and pathways has shown that most genes associated with myogenesis decrease their expression during the regeneration. The only exception is the genes united by the GO term “heart valve development”. This may indicate the antiquity of mechanisms of mesodermal structure transformation, which was co-opted into various morphogeneses in deuterostomes. Two groups of genes that play a key role in the regeneration have been analyzed: transcription factors and matrix metalloproteinases. A total of six transcription factor genes (Ef-HOX5, Ef-ZEB2, Ef-RARB, Ef-RUNX1, Ef-SOX17, and Ef-ZNF318) and seven matrix metalloproteinase genes (Ef-MMP11, Ef-MMP13, Ef-MMP13-1, Ef-MMP16-2, Ef-MMP16-3, Ef-MMP24, and Ef-MMP24-1) showing differential expression during myogenesis have been revealed. The identified genes are assumed to be involved in the muscle regeneration in holothurians.

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Mitchell, Emily, Michael Spencer Chapman, Nicholas Williams, Kevin J. Dawson, Nicole Mende, Emily Calderbank, Hyunchul Jung, et al. "Clonal Dynamics of Normal Haematopoiesis with Human Ageing." Blood 138, Supplement 1 (November 5, 2021): 598. http://dx.doi.org/10.1182/blood-2021-150152.

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Abstract The haematopoietic system manifests several age-associated phenotypes including anaemia; loss of regenerative capacity, especially in the face of insults such as infection, chemotherapy or blood loss; and increased risk of clonal haematopoiesis and blood cancers. The cellular alterations that underpin these age-related phenotypes, which typically manifest in individuals aged over 70, remain elusive. We aimed to investigate whether changes in HSC population structure with age might underlie any aspects of haematopoietic system ageing. We sequenced 3579 genomes from single-cell-derived colonies of haematopoietic stem cell/multipotent progenitors (HSC/MPPs) from 10 haematologically normal subjects aged 0-81 years. HSC/MPPs accumulated 17 somatic mutations/year after birth with no increased rate of mutation accumulation in the elderly. HSC/MPP telomere length declined by 30 bp/yr. In cord blood and adults aged <65, a small proportion of HSC/MPPs had unexpectedly long telomeres, as assessed using several criteria for outliers. The proportion of cells with unexpectedly long telomeres reduced in frequency with age. Given that telomeres shorten at cell division, these outlier cells have presumably undergone fewer historic cell divisions, supporting the existence of a rare population of dormant HSCs in humans that declines in frequency with age. To interrogate changes in HSC population structure with age, we used the pattern of unique and shared mutations between the sampled cells from each individual to reconstruct their phylogenetic relationships. The frequency of branch-points (known as coalescences) in phylogenetic trees in a neutrally evolving, well-mixed population of somatic cells is primarily determined by the product of population size and time between symmetric self-renewal cell divisions (Nt). Smaller populations and more frequent symmetric divisions both increase the density of coalescences. Specific clones can come to dominate either through neutral drift or positive selection. We found that haematopoiesis in adults aged <65 was polyclonal, with high indices of clonal diversity. The number and pattern of coalescent events in the phylogenies showed that a stable population of 20,000 to 200,000 HSC/MPPs was contributing evenly to blood production in young adult life. In contrast, haematopoiesis in individuals aged >75 showed profoundly decreased clonal diversity. In each elderly subject, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before age 40, but only 22% had known driver mutations. We used the ratio of non-synonymous to synonymous mutations (dN/dS) to identify any excess of non-synonymous (driver) mutations in the dataset. This genome-wide selection analysis estimated that 1/34 to 1/12 non-synonymous mutations were drivers, occurring at a constant rate throughout life, such that the set of 300 - 400 HSC/MPPs sampled from each adult individual harboured around 100 driver mutations, over 10-fold higher than the number of known drivers we could identify. Novel drivers affected a wider pool of genes than identified in blood cancers. The genes DNMT3A, ZNF318 and HIST2H3D were identified as being under significant positive selection in HSC/MPPs, despite ZNF318 and HIST2H3D not being enriched in the setting of myeloid malignancies. Loss of Y chromosome conferred selective benefits on HSC/MPPs in males. Simulations from a simple model of haematopoiesis, with constant HSC population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure observed in the elderly, which could not be explained by neutral models incorporating drift alone. Our data supports the view that dramatically decreased clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently known. By old age the majority of HSCs harbour at least one driver mutation. With such ubiquity of driver mutations, selected purely for their competitive advantage within the stem cell compartment, and with the wholesale rewiring of cellular pathways they induce, it is feasible that they may contribute to age-related phenotypes beyond the increased risk of blood cancer. Disclosures Spencer: Wugen, Inc.: Consultancy, Other: Stock Options. Vassiliou: Kymab Ltd: Divested equity in a private or publicly-traded company in the past 24 months; STRM.BIO: Consultancy; Astrazeneca: Consultancy. Kent: STRM.bio: Research Funding. Campbell: Mu Genomics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees.

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Sobocińska, Joanna, Joanna Nowakowska, Sara Molenda, Anna Olechnowicz, Kacper Guglas, Joanna Kozłowska-Masłoń, Urszula Kazimierczak, et al. "Zinc Finger Proteins in Head and Neck Squamous Cell Carcinomas: ZNF540 May Serve as a Biomarker." Current Oncology 29, no. 12 (December 16, 2022): 9896–915. http://dx.doi.org/10.3390/curroncol29120779.

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Head and neck squamous cell carcinoma (HNSCC) is one of the ten most common cancers. Most cancer cases originate from alcohol and tobacco consumption. However, studies have demonstrated that human papillomavirus (HPV) infection, particularly HPV-16, may also significantly influence disease progression. The KRAB-ZNF family of genes is involved in epigenetic suppression, and its involvement in carcinogenesis is the subject of extensive studies. The available literature data demonstrate that they may play different roles, both as tumor suppressors and oncogenes. In this study, six ZNF genes, ZFP28, ZNF132, ZNF418, ZNF426, ZNF540, and ZNF880, were tested using several in silico approaches based on the TCGA and GEO datasets. Our analyses indicate that the expression of the analyzed ZNFs was significantly downregulated in tumor tissues and depended on tumor localization. The expression levels of ZNFs differed between HPV-positive vs. HPV-negative patients depending on the clinical-pathological parameters. More specifically, the patients with higher levels of ZNF418 and ZNF540 showed better survival rates than those with a lower expression. In addition, the level of ZNF540 expression in HPV-positive (HPV(+)) patients was higher than in HPV-negative (HPV(−)) patients (p < 0.0001) and was associated with better overall survival (OS). In conclusion, we demonstrate that ZNF540 expression highly correlates with HPV infection, which renders ZNF540 a potential biomarker for HNSCC prognosis and treatment.

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Dougherty, Michael P., Lynn P. Chorich, and Lawrence Clarke Layman. "Evaluation of Mayer-Rokitansky-Kuster-Hauser (MRKH) Patient Families by Whole Genome Sequencing." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A501—A502. http://dx.doi.org/10.1210/jendso/bvab048.1025.

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Abstract Introduction: MRKH is a characterized by the congenital absence of the uterus and vagina in 46,XX individuals. A subset of these patients also has associated renal, skeletal, cardiac and/or auditory defects. Familial cases suggest a genetic component, but to date only pathogenic variants in WNT4 and HNF1B have been confirmed. We hypothesize that de novo heterozygous variants in candidate genes will be present in some patients with MRKH. Methods: DNAs from 30 quads (an MRKH proband and three relatives) were subjected to whole genome sequencing (WGS), and heterozygous variants in coding regions with < 0.02 frequency were filtered by two different methods. In the first approach, variants were filtered by 1) top consequence variant (splice site, stop-gain, frameshift, and missense, respectively); 2) impact score; 3) mapping quality; 4) cytobands; 5) intolerance; 6) de novo variants; and 7) plausibility based on familial genotype. The second approach considered only heterozygous variants found in the proband and absent in all other family members, which were then filtered by top consequence (splice donor and acceptor sites, stop-gain, frameshift). Results: Five pedigrees were excluded for inadequate sequence in one or more individuals. 55,033 variants in coding regions with < 2% frequency were identified in the 25 remaining quads for analysis. Using the first approach, 42 candidate gene variants in 32 genes were identified - 12 splice variants, 10 stop-gains, 15 frameshift variants and 5 missense variants. Of these, MUC22 contained 2 missense variants from different families. Additionally, DICER1 had multiple splice variants and is essential for mouse urogenital tract development. In the second approach, 39 candidate genes were identified—6 splice variants in 6 genes, 18 stop-gains in 17 genes, and 17 frameshift variants in 16 genes. Zinc finger genes (ZNF418, ZNF646, ZNF135, and ZNF772) comprised the most frequent class of the 39 genes. Two genes (MIR4436A and ZNF418) contained attractive variants in two different families. Conclusion: WGS has been shown to improve detection of gene variants in coding regions, more so than whole exome sequencing (WES). We previously performed WES on 111 MRKH probands without family members and analyzed variants in candidate genes suggested by mouse and preliminary human studies. Interestingly, in this study, only three genes overlapped with previously suspected candidate genes. Here, we identified new candidates based upon potential deleteriousness. These candidate genes will be studied further in our families to determine their role in Mullerian development.

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Ishikawa, S., M. Kai, Y. Takei, K. Okui, T. Takahashi, M. Suzuki, M. Ogawa, and Y. Nakamura. "Isolation and mapping of a human zinc finger gene (ZNF188) homologous to ZNF187, a serum-response-element binding protein." Cytogenetic and Genome Research 77, no. 3-4 (1997): 185–89. http://dx.doi.org/10.1159/000134572.

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Yan, Feng-Juan, Yong-Jian Wang, Shi-Ran Yan, Jun Lu, and Yuan-Lin Zheng. "ZNF300 stimulates fatty acid oxidation and alleviates hepatosteatosis through regulating PPARα." Biochemical Journal 476, no. 2 (January 31, 2019): 385–404. http://dx.doi.org/10.1042/bcj20180517.

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Abstract ZNF300 plays an important role in the regulation of HBV-related hepatocellular carcinoma. However, little is known about the role of ZNF300 in lipid metabolism and NAFLD. In the present study, we observed that ZNF300 expression was markedly decreased in free fatty acid (FFA)-induced fatty liver. Overexpressed ZNF300 alleviated hepatic lipid accumulation, whereas knockdown of ZNF300 enhanced the FFA-induced lipid accumulation. Investigations of the underlying mechanisms revealed that ZNF300 directly binds to and regulates the PPARα expression, thus promoting fatty acid oxidation. Furthermore, bisulfite pyrosequencing PCR (BSP) analysis identified the hypermethylation status of ZNF300 gene in FFA-treated hepatocytes. Importantly, the suppression of ZNF300 could be blocked by DNA methyltransferase inhibitor (5-azadC) or DNMT3a-siRNA. These results suggested that ZNF300 plays an important role in hepatic lipid metabolism via PPARα promoting fatty acid oxidation and this effect might be blocked by DNMT3a-mediated methylation of ZNF300. Therefore, in addition to ZNF300 expression levels, the methylation status of this gene also has a potential as a prognostic biomarker.

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Pieraccioli, Marco, Sara Nicolai, Consuelo Pitolli, Massimiliano Agostini, Alexey Antonov, Michal Malewicz, Richard A. Knight, Giuseppe Raschellà, and Gerry Melino. "ZNF281 inhibits neuronal differentiation and is a prognostic marker for neuroblastoma." Proceedings of the National Academy of Sciences 115, no. 28 (June 25, 2018): 7356–61. http://dx.doi.org/10.1073/pnas.1801435115.

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Derangement of cellular differentiation because of mutation or inappropriate expression of specific genes is a common feature in tumors. Here, we show that the expression of ZNF281, a zinc finger factor involved in several cellular processes, decreases during terminal differentiation of murine cortical neurons and in retinoic acid-induced differentiation of neuroblastoma (NB) cells. The ectopic expression of ZNF281 inhibits the neuronal differentiation of murine cortical neurons and NB cells, whereas its silencing causes the opposite effect. Furthermore, TAp73 inhibits the expression of ZNF281 through miR34a. Conversely, MYCN promotes the expression of ZNF281 at least in part by inhibiting miR34a. These findings imply a functional network that includes p73, MYCN, and ZNF281 in NB cells, where ZNF281 acts by negatively affecting neuronal differentiation. Array analysis of NB cells silenced for ZNF281 expression identified GDNF and NRP2 as two transcriptional targets inhibited by ZNF281. Binding of ZNF281 to the promoters of these genes suggests a direct mechanism of repression. Bioinformatic analysis of NB datasets indicates that ZNF281 expression is higher in aggressive, undifferentiated stage 4 than in localized stage 1 tumors supporting a central role of ZNF281 in affecting the differentiation of NB. Furthermore, patients with NB with high expression of ZNF281 have a poor clinical outcome compared with low-expressors. These observations suggest that ZNF281 is a controller of neuronal differentiation that should be evaluated as a prognostic marker in NB.

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Deng, Yu-Qin, Gang-Yong Kong, Song Li, Fen Li, and Si-Lu Wen. "Upregulation of lnc-ZNF281 Inhibits the Progression of Glioma via the AKT/GSK-3β/β-Catenin Signaling Pathway." Journal of Immunology Research 2021 (May 11, 2021): 1–9. http://dx.doi.org/10.1155/2021/5573071.

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The purpose of this study is to elucidate the roles and potential underlying mechanisms of long noncoding RNA lnc-ZNF281 in glioma. We performed qRT-PCR to detect the expression levels of lnc-ZNF281 in glioma tissues. The effects of lnc-ZNF281 on the proliferative and migrative abilities of T98G and HS683 glioma cells were examined by cell proliferation assay, colony formation assay, wound-healing assay, and transwell assay. Also, the effects of lnc-ZNF281 on AKT/GSK-3β/β-catenin pathway were analyzed. The results showed that the expression of lnc-ZNF281 in glioma tissues was decreased compared with normal tissues. lnc-ZNF281 overexpression inhibited the proliferative and migrative abilities of glioma cells, while lnc-ZNF281 knockdown obtained the opposite findings. Besides, overexpression of lnc-ZNF281 in glioma cells inactivated the AKT/GSK-3β/β-catenin signaling pathway. Furthermore, β-catenin activation reversed the suppressive effects of lnc-ZNF281 on glioma cells. Taken together, lnc-ZNF281 inhibits glioma cell proliferation and migration via AKT/GSK-3β/β-catenin pathway and may serve as a potential target for glioma treatment.

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Fahmé, Pia, Farah Ramadan, Diep Tien Le, Kieu-Oanh Nguyen Thi, Sandra E. Ghayad, Nader Hussein, Chantal Diaz, Martine Croset, Philippe Clézardin, and Pascale A. Cohen. "The Intricate Interplay between the ZNF217 Oncogene and Epigenetic Processes Shapes Tumor Progression." Cancers 14, no. 24 (December 8, 2022): 6043. http://dx.doi.org/10.3390/cancers14246043.

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The oncogenic transcription factor ZNF217 orchestrates several molecular signaling networks to reprogram integrated circuits governing hallmark capabilities within cancer cells. High levels of ZNF217 expression provide advantages to a specific subset of cancer cells to reprogram tumor progression, drug resistance and cancer cell plasticity. ZNF217 expression level, thus, provides a powerful biomarker of poor prognosis and a predictive biomarker for anticancer therapies. Cancer epigenetic mechanisms are well known to support the acquisition of hallmark characteristics during oncogenesis. However, the complex interactions between ZNF217 and epigenetic processes have been poorly appreciated. Deregulated DNA methylation status at ZNF217 locus or an intricate cross-talk between ZNF217 and noncoding RNA networks could explain aberrant ZNF217 expression levels in a cancer cell context. On the other hand, the ZNF217 protein controls gene expression signatures and molecular signaling for tumor progression by tuning DNA methylation status at key promoters by interfering with noncoding RNAs or by refining the epitranscriptome. Altogether, this review focuses on the recent advances in the understanding of ZNF217 collaboration with epigenetics processes to orchestrate oncogenesis. We also discuss the exciting burgeoning translational medicine and candidate therapeutic strategies emerging from those recent findings connecting ZNF217 to epigenetic deregulation in cancer.

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Kubanov, A. A., A. A. Kubanova, A. E. Karamova, and A. A. Mineyeva. "Prevalence of genetic risk factors of psoriasis among the population of the Russian Federation." Vestnik dermatologii i venerologii 90, no. 6 (December 24, 2014): 69–76. http://dx.doi.org/10.25208/0042-4609-2014-90-6-69-76.

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Goal. To assess the prevalence of polymorphisms of genes of the predisposition to psoriasis among the population of the Russian Federation. Materials and methods. The authors examined 546 psoriasis patients and 206 healthy people. The polymorphism of the following genes was assessed: genes encoding proteins of the signaling pathway of the nuclear transcription factor kappa-B - NF-κΒ (NFKBI, TRAF3IP2, TNFAIP3, REL, TYK2, TNIP1, IL-28RA) responsible for congenital immunity; genes participating in the IL-23 signaling pathway responsible for adaptive immunity (IL-23R, IL-12B); genes participating in the presentation of the antigen (ERAP1); genes responsible for skin barrier dysfunction (SERPINB8 ZNF313, ZNF816A). Peripheral blood leucocytes served as the DNA source. Polymorphisms of IL-23R, IL-28RA, SERPINB8, TRAF3IP2, TNFAIP3, REL, ZNF313, IL-12B, TNIP1, ZNF816A, ERAP1 genes were determined by the real-time PCR method; polymorphisms of NFKBI, TYK2 genes were determined by the RFLP assay (Restriction Fragment Length Polymorphism). Results. In psoriasis patients in the Russian Federation, statistically significant differences in the distribution of allele frequencies were determined for IL-23R-G/G, IL-23R-A/A, TRAF3IP2-A/A, TRAF3IP2-G/G, TNFAIP3-A/C, TNFAIP3-A/A, ZNF313-C/C, TYK2-T/T, TYK2-T/G, TNIP1-G/G, TNIP1-A/G, REL-A/A, ERAP1-G/G genotypes.

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Quinlan, Kate G. R., Marco Nardini, Alexis Verger, Pierangelo Francescato, Paul Yaswen, Daniela Corda, Martino Bolognesi, and Merlin Crossley. "Specific Recognition of ZNF217 and Other Zinc Finger Proteins at a Surface Groove of C-Terminal Binding Proteins." Molecular and Cellular Biology 26, no. 21 (August 28, 2006): 8159–72. http://dx.doi.org/10.1128/mcb.00680-06.

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ABSTRACT Numerous transcription factors recruit C-terminal binding protein (CtBP) corepressors. We show that the large zinc finger protein ZNF217 contacts CtBP. ZNF217 is encoded by an oncogene frequently amplified in tumors. ZNF217 contains a typical Pro-X-Asp-Leu-Ser (PXDLS) motif that binds in CtBP's PXDLS-binding cleft. However, ZNF217 also contains a second motif, Arg-Arg-Thr (RRT), that binds a separate surface on CtBP. The crystal structure of CtBP bound to an RRTGAPPAL peptide shows that it contacts a surface crevice distinct from the PXDLS binding cleft. Interestingly, both PXDLS and RRT motifs are also found in other zinc finger proteins, such as RIZ. Finally, we show that ZNF217 represses several promoters, including one from a known CtBP target gene, and mutations preventing ZNF217's contact with CtBP reduce repression. These results identify a new CtBP interaction motif and establish ZNF217 as a transcriptional repressor protein that functions, at least in part, by associating with CtBP.

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Thillainadesan, Gobi, Majdina Isovic, Esther Loney, Joseph Andrews, Marc Tini, and Joseph Torchia. "Genome Analysis Identifies the p15ink4b Tumor Suppressor as a Direct Target of the ZNF217/CoREST Complex." Molecular and Cellular Biology 28, no. 19 (July 14, 2008): 6066–77. http://dx.doi.org/10.1128/mcb.00246-08.

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ABSTRACT The ZNF217 oncoprotein is a constituent of a core transcriptional complex that includes CoREST, histone deacetylase 1/2, lysine demethylase 1, and the C-terminal binding protein 1/2. We have combined genome-wide expression profiling and chromatin immunoprecipitation with directed selection and ligation (ChIP-DSL) to identify a subset of genes directly regulated by ZNF217. Our results establish p15ink4b as a direct target of the ZNF217 complex. Downregulation of ZNF217 in MCF-7 breast cancer cells resulted in a dramatic increase in p15ink4b expression and coincided with increases in dimethylation of H3-K4 and, surprisingly, a decrease in K9/K14-H3 acetylation. Stimulation of HaCaT cells with transforming growth factor β (TGF-β) resulted in a release of ZNF217 and a concomitant binding of SMAD2 to the proximal promoter, which preceded increases in ink4b protein expression. Furthermore, the changes in chromatin marks at the p15ink4b promoter following TGF-β stimulation were similar to those observed following ZNF217 downregulation. Collectively, these results establish the ZNF217 complex as a novel negative regulator of the p15ink4b gene and may constitute an important link between amplification of ZNF217 and the loss of TGF-β responsiveness in breast cancer.

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Chen, Jing, Daniel J. DeAngelo, Jeffery L. Kutok, Ifor R. Williams, Benjamin H. Lee, Martha Wadleigh, Nicole Duclos, et al. "PKC412 Inhibits the ZNF198-FGFR1 Fusion Tyrosine Kinase and Is Efficacious in Treatment of t(8;13)(p11;q12) Associated Stem Cell Myeloproliferative Disease." Blood 104, no. 11 (November 16, 2004): 2549. http://dx.doi.org/10.1182/blood.v104.11.2549.2549.

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Abstract Human stem cell leukemia-lymphoma syndrome usually presents as a myeloproliferative disease (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase. Current empirically-derived cytotoxic chemotherapy is inadequate treatment of this disease. We hypothesized that small molecule inhibitors of the ZNF198-FGFR1 fusion would have therapeutic efficacy. We characterized the transforming activity of ZNF198-FGFR1 in hematopoietic cells in vitro and in vivo. Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human MPD phenotype. Transformation in these assays, and activation of the downstream effector molecules PLCγ, STAT5 and PI3K/AKT, required the proline-rich, but not the zinc-finger domains of ZNF198. A small molecule tyrosine kinase inhibitor, PKC412 (N-benzoyl-staurosporine) effectively inhibited ZNF198-FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198-FGFR1 transformed Ba/F3 cells. Furthermore, treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198-FGFR1 induced myeloproliferative disease. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious in treatment of progressive myeloproliferative disease with organomegaly. Therefore, PKC412 may be a useful therapy for treatment of human stem cell leukemia-lymphoma syndrome.

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Kasyapa, Chitta S., Padmaja Kunapuli, Lesleyann Hawthorn, and John K. Cowell. "Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease." Blood 107, no. 9 (May 1, 2006): 3693–99. http://dx.doi.org/10.1182/blood-2005-04-1505.

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The ZNF198/FGFR1 fusion kinase associated with an atypical myeloproliferative disease is constitutively activated and regulates several STAT transcription factors. We used oligonucleotide microarrays to compare the gene-expression profiles between HEK-293 cells that stably express either the ZNF198/FGFR1 chimeric protein or the wild-type ZNF198 gene. Expression of the plasminogen activator inhibitor-2 (PAI-2/SERPINB2) was highly increased in cells expressing the fusion gene. Western blot analysis demonstrated that HEK-293 cells do not express PAI-2 endogenously, but in ZNF198/FGFR1-expressing cells 2 molecular forms of PAI-2, which were 47 kDa and 32 kDa, were expressed intracellularly, and a 60-kDa form was secreted. Similarly, expression of ZNF198/FGFR1 in BaF/3 mouse hematopoietic cells also induced the expression of the PAI-2 protein. Immunoprecipitation analysis revealed that both intracellular forms of PAI-2 bind to the ZNF198/FGFR1 kinase. Treatment of HEK-293 and BaF/3 cells with TNF-α in the presence of cycloheximide, induced apoptosis in both cases. In contrast, HEK-293 and BaF/3 cells expressing ZNF198/FGFR1 were resistant to TNF-α-induced apoptosis. These observations suggest that expression of the ZNF198/FGFR1 fusion gene is associated with specific PAI-2-mediated resistance to apoptosis which may contribute to the highly malignant nature of leukemic cells carrying this fusion kinase gene.

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Wang, Minghao, Qiang Han, Zhe Su, and Xinmiao Yu. "Transcription Factor ZNF326 Upregulates the Expression of ERCC1 and HDAC7 and its Clinicopathologic Significance in Glioma." Laboratory Medicine 51, no. 4 (January 13, 2020): 377–84. http://dx.doi.org/10.1093/labmed/lmz075.

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Abstract Previous reports that we have coauthored have shown that transcription factor ZNF326 can upregulate the expression of ERCC1 and HDAC7, and downregulate the expression of LTBP4 and ZNF383 in lung-cancer cells. However, whether tissue-specificity of the ZNF326 function exists in glioma tissue remains unclear. In this study, overexpression or knockdown of ZNF326 in glioma cells caused upregulation or downregulation, respectively, of the protein and micro RNA (mRNA) levels of ERCC1 and HDAC7. The levels of LTBP4 and ZNF383 were not significantly changed. Immunohistochemical results showed that ZNF326 was not only highly expressed in glioma but was also positively correlated with the expression of ERCC1 and HDAC7. Moreover, the expression of ERCC1 and HDAC7 was enhanced with the increase in tumor grade. However, there was no correlation between ZNF326 and the expression of LTBP4 and ZNF383. Therefore, the detection of ZNF326, ERCC1, and HDAC7 expressions was useful for identifying different grades of glioma.

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Qin, Xi, Rui Su, Lu Yang, Anthony K. N. Chan, Xiaolan Deng, Ying Qing, Lars Klemm, Markus Müschen, Chun-Wei David Chen, and Jianjun Chen. "Identification of ZNF217 As an Essential Oncogenic Gene in B-Cell Acute Lymphoblastic Leukemia By CRISPR/Cas9-Based Library Screening." Blood 134, Supplement_1 (November 13, 2019): 1465. http://dx.doi.org/10.1182/blood-2019-129849.

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Background and Significance Although the prognosis of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has been significantly improved in recent years, adult patients continue to have dismal survival. This is partially due to the fact that adult patients tend to have more unfavorable cytogenetic characteristics such as MLL-AF4 fusion and BCR-ABL1 fusion. N6-methyladenosine (m6A) is the most prevalent epigenetic modification on eukaryotic messenger RNA (mRNA), which plays important roles in many fundamental bioprocesses. The aberrant regulation of m6A modification is crucial for the initiation and progression of various cancers including acute myeloid leukemia (AML). However, the studies of m6A modification in B-ALL have been limited. Therefore, we began with the screening of essential m6A regulators in B-ALL with unfavorable cytogenetic characteristics. Zinc Finger Protein 217 (ZNF217) is not only a Kruppel-like family of transcription factor but also a versatile m6A regulator. Although ZNF217 has been identified as a candidate oncogene and therapeutic target in many solid tumors, the potential function of ZNF217 in leukemia, especially in B-ALL, remains unknown. Experimental Approach and Results To determine which m6A machinery associated genes play essential roles in the survival/viability of B-ALL cells, we performed CRISPR/Cas9-based library screening using single-cloned B-ALL cells expressing Cas9. The sgRNA library contained sgRNAs targeting all the reported m6A machinery associated genes (including METTL3, METTL14, FTO; 25 sgRNAs per gene), 11 common essential genes, and scramble controls. The screening results suggested a set of m6A machinery associated genes, especially ZNF217, might be essential for the survival of B-ALL cells. To further rank these genes by their essentiality in B-ALL, we performed Model-based Analysis of Genome-wide CRISPR-Cas9 Knockout (MAGeCK). In our MAGeCK negative-selection ranking, ZNF217 was ranked as the top 1 candidate, indicating ZNF217 might be the most essential m6A regulator in B-ALL. In agreement with these results, ZNF217 is also highly expressed in B-ALL. We analyzed the published gene expression datasets and found ZNF217 is highly expressed in B-ALL patients with different cytogenetic changes, including MLL-AF4 fusion and BCR-ABL1 fusion, compared to normal CD19+CD10+ B-cell progenitors. To further validate the function of ZNF217, we perform growth competition experiments using B-ALL cells with either MLL-AF4 fusion or BCR-ABL1 fusion. We found that knockout of ZNF217 significantly decreased the competitive fitness of both B-ALL subtypes. In addition, we also found that knockout of ZNF217 in AML cells did not show significant effect on cell survival, suggesting the function of ZNF217 may be specific in B-lineage. Conclusions In summary, by use of CRISPR-Cas9 screening, we identified ZNF217 as an essential gene in B-ALL cells. We found ZNF217 is highly expressed in various subtypes of B-ALL patients, and our data suggest that ZNF217 is required for the survival of B-ALL cells, but not that of AML cells. Overall, our data indicate that ZNF217 plays an essential oncogenic role in B-ALL. Figure Legend A. Experimental scheme of CRISPR/Cas9-based library screening B. Growth competition assays using B-ALL cells (left) and AML cells (right) Figure Disclosures Chen: Genovel Biotech Corp: Other: scientific founder and Chairman.

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Li, Changhong, Peijun Xia, Yijuan Ma, Xinyue Zhang, and Yijia Liu. "Expression pattern of ZNF33B in bovine ovaries and the effect of its polymorphism on superovulation traits." Archives Animal Breeding 65, no. 1 (February 22, 2022): 69–77. http://dx.doi.org/10.5194/aab-65-69-2022.

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Abstract. ZNF33B belongs to recently duplicated Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs), which is widely present in various organs, and some evidence showed that its expression is altered in the ovary undergoing superovulation. In this study, the expression of ZNF33B in ovary and early embryo was determined by immunohistochemistry and immunofluorescence techniques. Results showed that the expression of ZNF33B in the ovary was mainly in the cytoplasm of oocytes and granulosa luteal cells of ovarian corpus luteum and significantly reduced during follicular ovulation to luteal degeneration. The expression of ZNF33B in the early embryo transferred from the nucleus to the whole cell, suggesting that the expression of ZNF33B is spatiotemporally specific. Then, in combination with the single nucleotide polymorphism (SNP) database, the g.-61G>T mutant of the 5′-untranslated region (5′ UTR) of the ZNF33B gene was screened out from 556 Changbaishan black cattle, and the frequency of the mutant gene was counted. The statistics of superovulation and superovulation traits confirmed significant differences between the two genotypes in the quantity and quality of oocytes obtained after superovulation. This study confirmed, for the first time, the effect of ZNF33B gene polymorphism on superovulation traits and suggested that the mutation could provide a basis for cattle breeding and improving animal fertility.

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Lu, Zhaojin, Zepeng Zheng, Yufen Xu, Chenlu Wang, Yueling Lin, Kun Lin, LanYan Fu, et al. "The Associated of the Risk of IVIG Resistance in Kawasaki Disease with ZNF112 Gene and ZNF180 Gene in a Southern Chinese Population." Journal of Inflammation Research Volume 15 (September 2022): 5053–62. http://dx.doi.org/10.2147/jir.s378080.

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Laudadio, Ilaria, Alex Bastianelli, Valerio Fulci, Claudia Carissimi, Eleonora Colantoni, Francesca Palone, Roberta Vitali, et al. "ZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis." International Journal of Molecular Sciences 23, no. 18 (September 6, 2022): 10261. http://dx.doi.org/10.3390/ijms231810261.

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Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear. ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis.

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Santos, Katheryn, Qingchun Jin, Peter G. Miller, Ashka Patel, Gregory J. Kirkner, Janet L. Files, Melissa E. Hughes, et al. "Abstract P3-08-01: Clonal hematopoiesis of indeterminate potential (CHIP) in metastatic triple negative breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–08–01—P3–08–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-08-01.

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Abstract Background. Patients (pts) with metastatic triple negative breast cancer (mTNBC) receive serial cytotoxic chemotherapy regimens, often with cumulative myelosuppressive effects, impairing treatment tolerance. Clonal hematopoiesis of indeterminate potential (CHIP) refers to the detection of somatic mutations in genes recurrently mutated in hematologic malignancies in the blood of adults with no evident hematologic abnormalities. Little is known about the natural history of CHIP after breast cancer treatment. We sought to characterize CHIP in pts undergoing treatment for mTNBC. Methods. In this retrospective cohort study we identified 149 pts with biopsy-proven mTNBC at a single tertiary care institution with at least one blood sample collected within six months of metastatic diagnosis. We performed targeted sequencing of cryopreserved peripheral blood mononuclear cell (PBMC)-derived genomic DNA and defined CHIP as the presence of at least one pathogenic somatic mutation present at variant allelic fraction (VAF) of 0.02-0.35. We assessed the relationship between CHIP status and overall survival (OS), demographics, clinicopathologic features, germline mutation status, and type and timing of therapy. Results. We identified 27 unique CHIP variants across 22/149 pts (15%) within six months of metastatic diagnosis. Frequency of mutated genes were as follows: DNMT3A (n=15), PPM1D (n=4), TP53 (n=3), TET2 (n=2), SRCAP (n=1), ZBTB33 (n=1), ZNF318 (n=1). Median follow-up in the cohort was 37.9 months (IQR: 23.9-Not reached). The median age at time of blood draw was 55 years (IQR: 8.5) for pts with CHIP vs. 51 years (IQR: 16.5) for pts without CHIP. Ten (45%) pts with CHIP and 47 (37%) pts without CHIP were current or former smokers. Two (9%) pts with CHIP and 10 (7.9%) pts without CHIP were known germline mutation carriers of BRCA1, BRCA2 or PALB2. Twenty-two (100%) pts with CHIP and 124 (98%) pts without CHIP had received systemic chemotherapy for mTNBC prior to blood draw. There were no significant differences in type of chemotherapy regimen received between patients with or without CHIP. Twenty (90.9%) pts with CHIP vs. 96 (75.6%) of pts without CHIP had received radiation therapy prior to blood draw. Pts with CHIP had similar OS to those without CHIP (median OS 7.75 [2.20-31.7] vs. 9.33 [8.02-11.73] months). No pts developed therapy-related myeloid neoplasms (t-MN) or died of complications of cardiac disease. Conclusions. Pts with mTNBC had a higher frequency of CHIP than previously reported in age-matched healthy populations, but similar CHIP prevalence to what has been seen in cohorts of pts with solid tumors. Our study assessed for the presence of CHIP at only a single time point early in the metastatic course, but serial blood sampling later in treatment might reveal additional cases of CHIP. Though this cohort of patients with life-limiting mTNBC was small, presence of CHIP in the first six months of metastatic diagnosis was not associated with worse survival. Citation Format: Katheryn Santos, Qingchun Jin, Peter G. Miller, Ashka Patel, Gregory J. Kirkner, Janet L. Files, Melissa E. Hughes, Samantha M. Stokes, Nabihah Tayob, Daniel G. Stover, Christopher J. Gibson, Eric P. Winer, Nancy U. Lin, Judy E. Garber, Heather A. Parsons. Clonal hematopoiesis of indeterminate potential (CHIP) in metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-08-01.

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Nicolai, Sara, Robert Mahen, Giuseppe Raschellà, Alberto Marini, Marco Pieraccioli, Michal Malewicz, Ashok R. Venkitaraman, and Gerry Melino. "ZNF281 is recruited on DNA breaks to facilitate DNA repair by non-homologous end joining." Oncogene 39, no. 4 (September 30, 2019): 754–66. http://dx.doi.org/10.1038/s41388-019-1028-7.

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Abstract Efficient repair of DNA double-strand breaks (DSBs) is of critical importance for cell survival. Although non-homologous end joining (NHEJ) is the most used DSBs repair pathway in the cells, how NHEJ factors are sequentially recruited to damaged chromatin remains unclear. Here, we identify a novel role for the zinc-finger protein ZNF281 in participating in the ordered recruitment of the NHEJ repair factor XRCC4 at damage sites. ZNF281 is recruited to DNA lesions within seconds after DNA damage through a mechanism dependent on its DNA binding domain and, at least in part, on poly-ADP ribose polymerase (PARP) activity. ZNF281 binds XRCC4 through its zinc-finger domain and facilitates its recruitment to damaged sites. Consequently, depletion of ZNF281 impairs the efficiency of the NHEJ repair pathway and decreases cell viability upon DNA damage. Survival analyses from datasets of commonly occurring human cancers show that higher levels of ZNF281 correlate with poor prognosis of patients treated with DNA-damaging therapies. Thus, our results define a late ZNF281-dependent regulatory step of NHEJ complex assembly at DNA lesions and suggest additional possibilities for cancer patients’ stratification and for the development of personalised therapeutic strategies.

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Reiter, Andreas, Jastinder Sohal, Shashikant Kulkarni, Andrew Chase, Donald H. C. Macdonald, Ricardo C. T. Aguiar, Cristina Gonçalves, et al. "Consistent Fusion of ZNF198 to the Fibroblast Growth Factor Receptor-1 in the t(8;13)(p11;q12) Myeloproliferative Syndrome." Blood 92, no. 5 (September 1, 1998): 1735–42. http://dx.doi.org/10.1182/blood.v92.5.1735.

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Abstract The 8p11 myeloproliferative syndrome is a rare, aggressive condition associated with reciprocal translocations of chromosome band 8p11, most commonly the t(8;13)(p11;q12). To identify the genes involved in this translocation, we used fluorescence in situ hybridization (FISH) analysis to show that the chromosome 8 breakpoints fell within YAC 899e2 and that the chromosome 13 breakpoints are clustered in a region flanked by YACs 929f11 and 911h8. FISH using chromosome 13 PAC clones indicated that the t(8;13) is not simply a reciprocal translocation but also involves an inversion of 13q11-12. Exon trapping of a PAC that spanned the chromosome 13 translocation breakpoints led to the identification of a gene, ZNF198, that detected rearranged bands when used as a probe against Southern blots of patient DNA. Conceptual translation of the full-length ZNF198 cDNA sequence predicts a protein of 1377 amino acids that shows significant homology to the DXS6673E/KIAA0385 and KIAA0425 proteins. Alignment of these three proteins revealed a novel, conserved Zn-finger–related motif (MYM domain) of the general form CX2C19-22CX3CX13-19CX2CX19-25FCX3CX3F/Y that is repeated five times in each protein. To identify the translocation partner gene on chromosome 8, 5′ and 3′ RACE polymerase chain reactions (PCRs) were performed on patient RNA with several combinations of ZNF198 primers. Clones were identified in which the ZNF198 was fused to exon 9 of the fibroblast growth factor receptor-1 (FGFR1), a gene known to map to 8p11. An identical ZNF198-FGFR1 fusion was detected in the three patients with a t(8;13) for whom RNA was available; reciprocal FGFR1-ZNF198 transcripts were not detected. Rearrangements of both ZNF198 and FGFR1 were found in two further patients by Southern blotting. ZNF198-FGFR1 includes the five MYM domains of ZNF198 and the intracellular tyrosine kinase domain of FGFR1. We hypothesize that this fusion leads to constitutive activation of the FGFR1 tyrosine kinase in a manner analogous to the activation of ABL by BCR in chronic myeloid leukemia. © 1998 by The American Society of Hematology.

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Reiter, Andreas, Jastinder Sohal, Shashikant Kulkarni, Andrew Chase, Donald H. C. Macdonald, Ricardo C. T. Aguiar, Cristina Gonçalves, et al. "Consistent Fusion of ZNF198 to the Fibroblast Growth Factor Receptor-1 in the t(8;13)(p11;q12) Myeloproliferative Syndrome." Blood 92, no. 5 (September 1, 1998): 1735–42. http://dx.doi.org/10.1182/blood.v92.5.1735.417k11_1735_1742.

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The 8p11 myeloproliferative syndrome is a rare, aggressive condition associated with reciprocal translocations of chromosome band 8p11, most commonly the t(8;13)(p11;q12). To identify the genes involved in this translocation, we used fluorescence in situ hybridization (FISH) analysis to show that the chromosome 8 breakpoints fell within YAC 899e2 and that the chromosome 13 breakpoints are clustered in a region flanked by YACs 929f11 and 911h8. FISH using chromosome 13 PAC clones indicated that the t(8;13) is not simply a reciprocal translocation but also involves an inversion of 13q11-12. Exon trapping of a PAC that spanned the chromosome 13 translocation breakpoints led to the identification of a gene, ZNF198, that detected rearranged bands when used as a probe against Southern blots of patient DNA. Conceptual translation of the full-length ZNF198 cDNA sequence predicts a protein of 1377 amino acids that shows significant homology to the DXS6673E/KIAA0385 and KIAA0425 proteins. Alignment of these three proteins revealed a novel, conserved Zn-finger–related motif (MYM domain) of the general form CX2C19-22CX3CX13-19CX2CX19-25FCX3CX3F/Y that is repeated five times in each protein. To identify the translocation partner gene on chromosome 8, 5′ and 3′ RACE polymerase chain reactions (PCRs) were performed on patient RNA with several combinations of ZNF198 primers. Clones were identified in which the ZNF198 was fused to exon 9 of the fibroblast growth factor receptor-1 (FGFR1), a gene known to map to 8p11. An identical ZNF198-FGFR1 fusion was detected in the three patients with a t(8;13) for whom RNA was available; reciprocal FGFR1-ZNF198 transcripts were not detected. Rearrangements of both ZNF198 and FGFR1 were found in two further patients by Southern blotting. ZNF198-FGFR1 includes the five MYM domains of ZNF198 and the intracellular tyrosine kinase domain of FGFR1. We hypothesize that this fusion leads to constitutive activation of the FGFR1 tyrosine kinase in a manner analogous to the activation of ABL by BCR in chronic myeloid leukemia. © 1998 by The American Society of Hematology.

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Xiao, Sheng, Jennifer G. McCarthy, Jon C. Aster, and Jonathan A. Fletcher. "ZNF198–FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain." Blood 96, no. 2 (July 15, 2000): 699–704. http://dx.doi.org/10.1182/blood.v96.2.699.

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Abstract An acquired chromosomal translocation, t(8;13)(p11;q11-12), observed in a distinctive type of stem cell leukemia/lymphoma syndrome, leads to the fusion of the 5′ portion of ZNF198 and the 3′ portion of FGFR1. ZNF198–FGFR1 fusion transcripts encode 4 to 10 zinc fingers, a proline-rich region, and the intracellular portion of the FGFR1 (fibroblast growth factor receptor 1) receptor tyrosine kinase. We demonstrate that the ZNF198 proline-rich region constitutes a novel self-association domain. When fused to the intracellular domain of FGFR1, the ZNF198 proline-rich region is sufficient to cause oligomerization, FGFR1 tyrosine kinase activation, and transformation of Ba/F3 cells to IL-3 independent growth.

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Xiao, Sheng, Jennifer G. McCarthy, Jon C. Aster, and Jonathan A. Fletcher. "ZNF198–FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain." Blood 96, no. 2 (July 15, 2000): 699–704. http://dx.doi.org/10.1182/blood.v96.2.699.014k53_699_704.

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An acquired chromosomal translocation, t(8;13)(p11;q11-12), observed in a distinctive type of stem cell leukemia/lymphoma syndrome, leads to the fusion of the 5′ portion of ZNF198 and the 3′ portion of FGFR1. ZNF198–FGFR1 fusion transcripts encode 4 to 10 zinc fingers, a proline-rich region, and the intracellular portion of the FGFR1 (fibroblast growth factor receptor 1) receptor tyrosine kinase. We demonstrate that the ZNF198 proline-rich region constitutes a novel self-association domain. When fused to the intracellular domain of FGFR1, the ZNF198 proline-rich region is sufficient to cause oligomerization, FGFR1 tyrosine kinase activation, and transformation of Ba/F3 cells to IL-3 independent growth.

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Fang, Yuan, Xu Han, Jianang Li, Tiantao Kuang, and Wenhui Lou. "HEATR1 Deficiency Promotes Chemoresistance via Upregulating ZNF185 and Downregulating SMAD4 in Pancreatic Cancer." Journal of Oncology 2020 (May 26, 2020): 1–10. http://dx.doi.org/10.1155/2020/3181596.

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Objective. To discover the correlated gene with HEATR1 in regulating chemoresistance of gemcitabine. Methods. Gene chip analysis was performed to find out differential genes between HEATR1-KD and control groups. The top 20 genes were subjected to high-content screening, and functional assay was implemented. Gene expression profiling was carried out to find the downstream target. Immunohistochemistry and survival analysis were performed. Results. ZNF185 fold change (4.5285) was the most significant between the HEATR1-KD and control groups. Knocking down ZNF185 could promote the chemosensitivity, apoptosis, and proliferative inhibition, with SMAD4 significantly upregulated. Patients with high HEATR1 and SMAD4 or low ZNF185 exhibited better survival. Conclusion. HEATR1, ZNF185, and SMAD4 could affect the chemosensitivity of gemcitabine and may be the indicators of gemcitabine selection in the chemotherapy of pancreatic cancer.

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Ramírez-Ramírez, Ruth, Melva Gutiérrez-Angulo, Jorge Peregrina-Sandoval, José Miguel Moreno-Ortiz, Ramon Antonio Franco-Topete, Felipe de Jesús Cerda-Camacho, and Maria de la Luz Ayala-Madrigal. "Somatic deletion of KDM1A/LSD1 gene is associated to advanced colorectal cancer stages." Journal of Clinical Pathology 73, no. 2 (August 30, 2019): 107–11. http://dx.doi.org/10.1136/jclinpath-2019-206128.

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AimsKDM1A/LSD1 and ZNF217 are involved in a protein complex that participates in transcriptional regulation. ZNF217 has been analysed in numerous cancers and its amplification has been associated with advanced stages of disease; however, a similar role for KDM1A/LSD1 has not been uncovered. In this study, we estimated the number of KDM1A/LSD1 and ZNF217 gene copies in tissue samples from patients diagnosed with colorectal cancer (CRC), as well as its association with clinicopathological features in patients with CRC.MethodsParaffin-embedded tumour samples from 50 patients with CRC with a histopathological diagnosis of CRC were included. The number of copies of KDM1A/LSD1 and ZNF217 genes was determined by fluorescence in situ hybridisation (FISH). We also analysed the association between copy numbers of selected genes and clinicopathological data based on multivariate analysis.ResultsDeletion of the KDM1A/LSD1 gene occurred in 19 samples (38%), whereas ZNF217 gene amplification was identified in 11 samples (22%). We found a significant association between lymph node metastasis or advanced tumour stage and KDM1A/LSD1 gene deletion (p value=0.0003 and p value=0.011, respectively).ConclusionsKDM1A/LSD1 gene deletion could be considered a novel prognostic biomarker of late-stage CRC.

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Mantsou, Aglaia, Evangelia Koutsogiannouli, Costas Haitoglou, Athanasios G. Papavassiliou, and Nikolaos A. Papanikolaou. "Regulation of expression of the p21CIP1 gene by the transcription factor ZNF217 and MDM2." Biochemistry and Cell Biology 94, no. 6 (December 2016): 560–68. http://dx.doi.org/10.1139/bcb-2016-0026.

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Using mouse double minute 2 (MDM2) protein-specific affinity chromatography and mass spectrometry, we have isolated the protein product of the oncogene znf217, which is a transcription factor and a component of a Hela-S-derived HDAC1 complex, as a novel MDM2-interacting protein. When co-expressed in cultured cancer cells, ZNF217 forms a complex with MDM2 and its ectopic over-expression reduces the steady-state levels of acetylated p53 in cell lines, suppressing its ability to activate the expression of a p21 promoter construct. In-silico analysis of the p21 promoter revealed the presence of several ZNF217-binding sites. These findings suggest that MDM2 controls p21 expression by at least 2 mechanisms: through ZNF217-mediated recruitment of HDAC1/MDM2 activity, which inhibits p53 acetylation; and through direct interaction with its binding site(s) on the p21 promoter.

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Zhang, Shulong, Kaihua Zhu, Qi Han, Quan Wang, and Bin Yang. "lncRNA PCAT1 might coordinate ZNF217 to promote CRC adhesion and invasion through regulating MTA2/MTA3/Snai1/E-cadherin signaling." Cellular and Molecular Biology 67, no. 4 (January 2, 2022): 1–9. http://dx.doi.org/10.14715/cmb/2021.67.4.1.

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LncRNA prostate cancer-associated transcript 1 (PCAT1) is a well-known oncogene, but the mechanisms of exosomes PCAT1 in colorectal cancer (CRC) remain largely unknown. Thus, the mechanisms of exosomes lncRNA PCAT1 were investigated. The expressions of exosomes lncRNA PCAT1 in tissues from stage 0-I and stage II-III CRC patients, and intestinal epithelial cell line FHC and two CRC cell lines, HT29 and HCT8 were measured by real-time quantitative PCR. The effects of lncRNA PCAT1 on adhesion and invasion of two CRC cell lines were investigated by cell-matrix adhesion and transwell assays. In addition, the target of PCAT1 (ZNF217) was validated using an RNA immune precipitation assay. Finally, the protein levels of MTA2, MTA3, SNAI1, and E-cadherin in normal participants, stage 0-I and stage II-III CRC patients, as well as two cell lines with stable ZNF217 knockdown were investigated by western blotting. The plasma exosomal lncRNA PCAT1 was found to be significantly increased in the CRC tissues and cell lines. In addition, lncRNA PCAT1 knockdown significantly inhibited the adhesion and invasion of HT29 and HCT8 cells. RIP assay results showed lncRNA PCAT1 could target ZNF217, and downregulation of lncRNA PCAT1 could decrease the protein expressions of ZNF217 in two CRC cells lines. Moreover, ZNF217 knockdown significantly decreased MTA2, MTA3, and SNAI1 expressions, but increased E-cadherin expressions in both CRC cells lines. Exosomal lncRNA PCAT1 can promote the adhesion and invasion of CRC cells, and PCAT1 overexpression may lead to ZNF217 upregulation that regulates EMT-related MTA2/MTA3/Snai1/E-cadherin signaling

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Ren, Mingqiang, Xiurong Li, and John K. Cowell. "Genetic fingerprinting of the development and progression of T-cell lymphoma in a murine model of atypical myeloproliferative disorder initiated by the ZNF198–fibroblast growth factor receptor-1 chimeric tyrosine kinase." Blood 114, no. 8 (August 20, 2009): 1576–84. http://dx.doi.org/10.1182/blood-2009-03-212704.

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AbstractA mouse model of human ZNF198–fibroblast growth factor receptor-1 (FGFR1) stem cell leukemia lymphoma has been developed to investigate mechanisms of oncogenesis and progression. Using array-based comparative genomic hybridization, we followed disease progression after serial transplantation of ZNF198-FGFR1–transformed stem cells that give rise to a distinct myeloproliferative disorder and T-lymphoblastic leukemia. A consistent, frequently homozygous, chr14:53880459-55011545 deletion, containing the T-cell receptor α and δ genes, was identified in the bone marrow, spleen, and lymph nodes in all cases. The absence of cell-surface T-cell receptor α in tumor cells precludes CD3 recruitment, resulting in loss of a functional T-cell receptor complex, supporting the idea that prevention of maturation of CD4+/CD8+ double-positive immature T cells is important in ZNF198-FGFR1 disease development. Up-regulation of the B-cell line 2, interleukin 7 receptor α and interleuking 2 receptor α prosurvival genes in these undifferentiated tumor precursor cells suggests one mechanism that allows them to escape apoptosis in the thymus. Thus, we have defined an important event in the process of ZNF198-FGFR1–induced T-cell leukemia.

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Gao, Yiwen, Nan Zhang, Chunmei Lv, Na Li, Xueqin Li, and Weiwei Li. "lncRNA SNHG1 Knockdown Alleviates Amyloid-β-Induced Neuronal Injury by Regulating ZNF217 via Sponging miR-361-3p in Alzheimer’s Disease." Journal of Alzheimer's Disease 77, no. 1 (September 1, 2020): 85–98. http://dx.doi.org/10.3233/jad-191303.

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Background: Long noncoding RNAs have been proven to play an important role in the progression of Alzheimer’s disease (AD). However, the function of small nucleolar RNA host gene 1 (SNHG1) in AD progression remains to be studied. Objective: To explore the role of SNHG1 in AD progression and clarify its potential mechanism. Methods: Amyloid β-protein (Aβ) was used to construct an AD cell model in vitro. The expression levels of SNHG1 and miR-361-3p were determined by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit 8 assay and flow cytometry. The levels of apoptosis-related proteins and zinc finger gene 217 (ZNF217) protein were evaluated by western blot analysis. Additionally, the contents of inflammatory cytokines and oxidative stress markers were tested by enzyme-linked immunosorbent assay. Furthermore, dual-luciferase reporter and RNA immunoprecipitation assays were used to verify the interaction between miR-361-3p and SNHG1 or ZNF217. Results: Aβ could induce cell injury, while resveratrol could reverse this effect. SNHG1 expression was positively regulated by Aβ and negatively regulated by resveratrol. SNHG1 knockdown could reverse the promotion effect of Aβ on cell injury. Moreover, SNHG1 sponged miR-361-3p, and miR-361-3p targeted ZNF217. Additionally, miR-361-3p overexpression reversed the promotion effect of SNHG1 overexpression on cell injury, and ZNF217 silencing also reversed the promotion effect of miR-361-3p inhibitor on cell injury. Conclusion: SNHG1 promoted cell injury by regulating the miR-361-3p/ZNF217 axis, which might provide a theoretical basis for molecular therapy of AD.

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Capon, Francesca, Marie-José Bijlmakers, Natalie Wolf, Maria Quaranta, Ulrike Huffmeier, Michael Allen, Kirsten Timms, et al. "Identification of ZNF313 / RNF114 as a novel psoriasis susceptibility gene." Human Molecular Genetics 17, no. 13 (March 25, 2008): 1938–45. http://dx.doi.org/10.1093/hmg/ddn091.

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Zhu, Hua, Yaojuan Yang, Jun Gao, Huaping Tao, Chunsheng Qu, Jia Qu, and Jieguang Chen. "Area dependent expression of ZNF312 in human fetal cerebral cortex." Neuroscience Research 68, no. 1 (September 2010): 73–76. http://dx.doi.org/10.1016/j.neures.2010.05.007.

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El Abdellaoui-Soussi, Fadoua, Paula S. Yunes-Leites, Dolores López-Maderuelo, Fernando García-Marqués, Jesús Vázquez, Juan Miguel Redondo, and Pablo Gómez-del Arco. "Interplay between the Chd4/NuRD Complex and the Transcription Factor Znf219 Control Cardiac Cell Identity." International Journal of Molecular Sciences 23, no. 17 (August 24, 2022): 9565. http://dx.doi.org/10.3390/ijms23179565.

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The sarcomere regulates striated muscle contraction. This structure is composed of several myofibril proteins, isoforms of which are encoded by genes specific to either the heart or skeletal muscle. The chromatin remodeler complex Chd4/NuRD regulates the transcriptional expression of these specific sarcomeric programs by repressing genes of the skeletal muscle sarcomere in the heart. Aberrant expression of skeletal muscle genes induced by the loss of Chd4 in the heart leads to sudden death due to defects in cardiomyocyte contraction that progress to arrhythmia and fibrosis. Identifying the transcription factors (TFs) that recruit Chd4/NuRD to repress skeletal muscle genes in the myocardium will provide important information for understanding numerous cardiac pathologies and, ultimately, pinpointing new therapeutic targets for arrhythmias and cardiomyopathies. Here, we sought to find Chd4 interactors and their function in cardiac homeostasis. We therefore describe a physical interaction between Chd4 and the TF Znf219 in cardiac tissue. Znf219 represses the skeletal-muscle sarcomeric program in cardiomyocytes in vitro and in vivo, similarly to Chd4. Aberrant expression of skeletal-muscle sarcomere proteins in mouse hearts with knocked down Znf219 translates into arrhythmias, accompanied by an increase in PR interval. These data strongly suggest that the physical and genetic interaction of Znf219 and Chd4 in the mammalian heart regulates cardiomyocyte identity and myocardial contraction.

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Bijlmakers, Marie-jose, Jonathan Barker, Richard Trembath, and Francesca Capon. "F.11. Preliminary Characterization of the RNF114/ZNF313 Psoriasis Susceptibility Gene." Clinical Immunology 131 (2009): S96. http://dx.doi.org/10.1016/j.clim.2009.03.279.

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Lee, Dung-Fang, Martin J. Walsh, and Francesca Aguiló. "ZNF217/ZFP217 Meets Chromatin and RNA." Trends in Biochemical Sciences 41, no. 12 (December 2016): 986–88. http://dx.doi.org/10.1016/j.tibs.2016.07.013.

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Donaldson, Nickett S., Curtis L. Nordgaard, Christina C. Pierre, Kevin F. Kelly, Shaiya C. Robinson, Laura Swystun, Roberto Henriquez, Monica Graham, and Juliet M. Daniel. "Kaiso regulates Znf131-mediated transcriptional activation." Experimental Cell Research 316, no. 10 (June 10, 2010): 1692–705. http://dx.doi.org/10.1016/j.yexcr.2010.03.011.

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Li, Yongqing, Yuequn Wang, Wuzhou Yuan, Yun Deng, Chuanbing Zhu, and Xiushan Wu. "Advanced studies on human gene ZNF322." Frontiers of Biology in China 2, no. 4 (October 2007): 379–82. http://dx.doi.org/10.1007/s11515-007-0056-9.

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Demiroglu, Asuman, E. Joanna Steer, Carol Heath, Kerry Taylor, Mark Bentley, Steven L. Allen, Prasad Koduru, et al. "The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins." Blood 98, no. 13 (December 15, 2001): 3778–83. http://dx.doi.org/10.1182/blood.v98.13.3778.

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Abstract This report describes 2 patients with a clinical and hematologic diagnosis of chronic myeloid leukemia (CML) in chronic phase who had an acquired t(8;22)(p11;q11). Analysis by fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR) indicated that both patients were negative for the BCR-ABL fusion, but suggested that the BCR gene was disrupted. Further FISH indicated a breakpoint within fibroblast growth factor receptor 1 (FGFR1), the receptor tyrosine kinase that is known to be disrupted in a distinctive myeloproliferative disorder, most commonly by fusion to ZNF198. RT-PCR confirmed the presence in both cases of an in-frame messenger RNA fusion between BCR exon 4 and FGFR1 exon 9. Expression of BCR-FGFR1 in the factor-dependent cell line Ba/F3 resulted in interleukin 3-independent clones that grew at a comparable rate to cells transformed with ZNF198-FGFR1. The growth of transformed cells was inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002, the farnesyltransferase inhibitors L744832 and manumycin A, the p38 inhibitors SB202190 and SB203580 but not by the MEK inhibitor PD98059. The growth of BaF3/BCR-FGFR1 and BaF3/ZNF198-FGFR1 was not significantly inhibited by treatment with STI571, but was inhibited by SU5402, a compound with inhibitory activity against FGFR1. Inhibition with this compound was associated with decreased phosphorylation of ERK1/2 and BCR-FGFR1 or ZNF198-FGFR1, and was dose dependent with an inhibitory concentration of 50% of approximately 5 μM. As expected, growth of BaF3/BCR-ABL was inhibited by STI571 but not by SU5402. The study demonstrates that the BCR-FGFR1 fusion may occur in patients with apparently typical CML. Patients with constitutively active FGFR1 fusion genes may be amenable to treatment with specific FGFR1 inhibitors.

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Bruton, Rachel K., Peter Pelka, Katie L. Mapp, Gregory J. Fonseca, Joseph Torchia, Andrew S. Turnell, Joe S. Mymryk, and Roger J. A. Grand. "Identification of a Second CtBP Binding Site in Adenovirus Type 5 E1A Conserved Region 3." Journal of Virology 82, no. 17 (June 4, 2008): 8476–86. http://dx.doi.org/10.1128/jvi.00248-08.

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ABSTRACT C-terminal binding protein (CtBP) binds to adenovirus early region 1A (AdE1A) through a highly conserved PXDLS motif close to the C terminus. We now have demonstrated that CtBP1 also interacts directly with the transcriptional activation domain (conserved region 3 [CR3]) of adenovirus type 5 E1A (Ad5E1A) and requires the integrity of the entire CR3 region for optimal binding. The interaction appears to be at least partially mediated through a sequence (161RRNTGDP167) very similar to a recently characterized novel CtBP binding motif in ZNF217 as well as other regions of CR3. Using reporter assays, we further demonstrated that CtBP1 represses Ad5E1A CR3-dependent transcriptional activation. Ad5E1A also appears to be recruited to the E-cadherin promoter through its interaction with CtBP. Significantly, Ad5E1A, CtBP1, and ZNF217 form a stable complex which requires CR3 and the PLDLS motif. It has been shown that Ad513SE1A, containing the CR3 region, is able to overcome the transcriptional repressor activity of a ZNF217 polypeptide fragment in a GAL4 reporter assay through recruitment of CtBP1. These results suggest a hitherto-unsuspected complexity in the association of Ad5E1A with CtBP, with the interaction resulting in transcriptional activation by recruitment of CR3-bound factors to CtBP1-containing complexes.

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Fisher, Laura. "Retraction: Berberine alleviates amyloid beta-induced injury in Alzheimer’s disease by miR-107/ZNF217." RSC Advances 11, no. 9 (2021): 5001. http://dx.doi.org/10.1039/d1ra90031e.

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Rodriguez, Patricia Q., Asmundur Oddsson, Lwaki Ebarasi, Bing He, Kjell Hultenby, Annika Wernerson, Christer Betsholtz, Karl Tryggvason, and Jaakko Patrakka. "Knockdown of Tmem234 in zebrafish results in proteinuria." American Journal of Physiology-Renal Physiology 309, no. 11 (December 1, 2015): F955—F966. http://dx.doi.org/10.1152/ajprenal.00525.2014.

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Podocytes are highly specialized epithelial cells located at the outer aspects of the glomerular capillary tuft and critical components of the kidney filtration barrier. To maintain their unique features, podocytes express a number of proteins that are only sparsely found elsewhere in the body. In this study, we have identified four (Tmem234, Znf185, Lrrc49, and Slfn5) new highly podocyte-enriched proteins. The proteins are strongly expressed by podocytes, while other parts of the kidney show only weak or no expression. Tmem234, Slfn5, and Lrrc49 are located in foot processes, whereas Znf185 is found in both foot and major processes. Expressional studies in developing kidneys show that these proteins are first expressed at the capillary stage glomerulus, the same stage when the formation of major and foot processes begins. We identified zebrafish orthologs for Tmem234 and Znf185 genes and knocked down their expression using morpholino technology. Studies in zebrafish larvae indicate that Tmem234 is essential for the organization and functional integrity of the pronephric glomerulus filtration barrier, as inactivation of Tmem234 expression results in foot process effacement and proteinuria. In summary, we have identified four novel highly podocyte-enriched proteins and show that one of them, Tmem234, is essential for the normal filtration barrier in the zebrafish pronephric glomerulus. Identification of new molecular components of the kidney filtration barrier opens up possibilities to study their role in glomerulus biology and diseases.

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Gianotten, J., F. van der Veen, M. Alders, N. Leschot, M. Mannens, and M. Hoffer. "ZNF214: a candidate gene for impaired spermatogenesis." Fertility and Sterility 76, no. 3 (September 2001): S155—S156. http://dx.doi.org/10.1016/s0015-0282(01)02457-8.

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Law, David J., Edwin M. Labut, and Juanita L. Merchant. "Intestinal overexpression of ZNF148 suppresses ApcMin/+ neoplasia." Mammalian Genome 17, no. 10 (October 2006): 999–1004. http://dx.doi.org/10.1007/s00335-006-0052-4.

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Hui, Hong-xia, Zhong-wu Hu, Chao Jiang, Jian Wu, Yong Gao, and Xiao-wei Wang. "ZNF418 overexpression protects against gastric carcinoma and prompts a good prognosis." OncoTargets and Therapy Volume 11 (May 2018): 2763–70. http://dx.doi.org/10.2147/ott.s160802.

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Lee, M. G., J. Han, S. I. Jeong, N. G. Her, J. H. Lee, T. K. Ha, M. J. Kang, B. K. Ryu, and S. G. Chi. "XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313." Proceedings of the National Academy of Sciences 111, no. 43 (October 13, 2014): 15532–37. http://dx.doi.org/10.1073/pnas.1411746111.

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Jang, S., K. W. Lee, T. K. Magdalene, J. Ahn, M. G. Lee, and S. G. Chi. "XAF1 and ZNF313 complex stimulates ER stress-induced apoptosis via direct GRP78 inhibition." Annals of Oncology 30 (October 2019): v7. http://dx.doi.org/10.1093/annonc/mdz238.021.

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Li, Yongqing, Dan Yang, Yan Bai, Xiaoyang Mo, Wen Huang, Wuzhou Yuan, Zhaochu Yin, et al. "ZNF418, a novel human KRAB/C2H2 zinc finger protein, suppresses MAPK signaling pathway." Molecular and Cellular Biochemistry 310, no. 1-2 (December 15, 2007): 141–51. http://dx.doi.org/10.1007/s11010-007-9674-4.

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Kasyapa, Chitta S., Padmaja Kunapuli, and John K. Cowell. "HSPA1A is an important regulator of the stability and function of ZNF198 and its oncogenic derivative, ZNF198–FGFR1." Journal of Cellular Biochemistry 102, no. 5 (2007): 1308–17. http://dx.doi.org/10.1002/jcb.21362.

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Dong, Shaozhong, Sumin Kang, Ting-Lei Gu, Sean Kardar, Haian Fu, Sagar Lonial, Hanna Jean Khoury, Fadlo Khuri, and Jing Chen. "14–3-3 integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1–transformed hematopoietic cells." Blood 110, no. 1 (July 1, 2007): 360–69. http://dx.doi.org/10.1182/blood-2006-12-065615.

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Human 8p11 stem cell leukemia/lymphoma syndrome usually presents as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase that plays a pathogenic role in hematopoietic transformation. We found that ZNF198-FGFR1 activated both the AKT and mitogen activated protein kinase (MAPK) prosurvival signaling pathways, resulting in elevated phosphorylation of the AKT target FOXO3a at T32 and BAD at S112, respectively. These phosphorylated residues subsequently sequestered the proapoptotic FOXO3a and BAD to 14–3-3 to prevent apoptosis. We used a peptide-based 14–3-3 competitive antagonist, R18, to disrupt 14–3-3–ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by ZNF198-FGFR1 compared with control cells. Moreover, purified recombinant transactivator of transcription (TAT)-conjugated R18 proteins effectively transduced into human leukemia cells and induced significant apoptosis in KG-1a cells expressing FGFR1OP2-FGFR1 fusion tyrosine kinase but not in control HL-60 and Jurkat T cells. Surprisingly, R18 was only able to dissociate FOXO3a, but not BAD as previously proposed, from 14–3-3 binding and induced apoptosis partially through liberation and reactivation of FOXO3a. Our findings suggest that 14–3-3 integrates prosurvival signals in FGFR1 fusion-transformed hematopoietic cells. Disrupting 14–3-3–ligand association may represent an effective therapeutic strategy to treat 8p11 stem cell MPD.

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Journal articles on the topic 'ZNF318'

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