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1.
Mol Cell ; 71(2): 244-255.e5, 2018 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-29983320

RESUMO

tRNAs are subject to numerous modifications, including methylation. Mutations in the human N7-methylguanosine (m7G) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and brain malformation, yet the molecular and cellular function in mammals is not well understood. We developed m7G methylated tRNA immunoprecipitation sequencing (MeRIP-seq) and tRNA reduction and cleavage sequencing (TRAC-seq) to reveal the m7G tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs is modified at a "RAGGU" motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs, implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian m7G tRNA methylome and highlights its essential role in ESCs with links to human disease.


Assuntos
Proteínas de Ligação ao GTP/genética , Guanosina/análogos & derivados , Metiltransferases/genética , RNA de Transferência/genética , Animais , Sequência de Bases , Diferenciação Celular/genética , Linhagem Celular , Autorrenovação Celular/genética , Células-Tronco Embrionárias , Proteínas de Ligação ao GTP/metabolismo , Guanosina/genética , Guanosina/metabolismo , Humanos , Metilação , Metiltransferases/metabolismo , Camundongos , Células-Tronco Embrionárias Murinas , Processamento Pós-Transcricional do RNA , RNA de Transferência/metabolismo
2.
Development ; 147(2)2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941704

RESUMO

WD40 proteins control many cellular processes via protein interactions. Drosophila Wuho (Wh, a WD40 protein) controls fertility, although the involved mechanisms are unclear. Here, we show that Wh promotion of Mei-p26 (a human TRIM32 ortholog) function maintains ovarian germ cell homeostasis. Wh and Mei-p26 are epistatically linked, with wh and mei-p26 mutants showing nearly identical phenotypes, including germline stem cell (GSC) loss, stem-cyst formation due to incomplete cytokinesis between GSCs and daughter cells, and overproliferation of GSC progeny. Mechanistically, Wh interacts with Mei-p26 in different cellular contexts to induce cell type-specific effects. In GSCs, Wh and Mei-p26 promote BMP stemness signaling for proper GSC division and maintenance. In GSC progeny, Wh and Mei-p26 silence nanos translation, downregulate a subset of microRNAs involved in germ cell differentiation and suppress ribosomal biogenesis via dMyc to limit germ cell mitosis. We also found that the human ortholog of Wh (WDR4) interacts with TRIM32 in human cells. Our results show that Wh is a regulator of Mei-p26 in Drosophila germ cells and suggest that the WD40-TRIM interaction may also control tissue homeostasis in other stem cell systems.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Células Germinativas/metabolismo , Homeostase , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , Sequência Conservada , Drosophila melanogaster/citologia , Evolução Molecular , Feminino , Fertilidade , Células Germinativas/citologia , Meiose , MicroRNAs/genética , MicroRNAs/metabolismo , Mitose , Modelos Biológicos , Mutação/genética , Ovário/citologia , Óvulo/citologia , Óvulo/metabolismo , Fenótipo , Ligação Proteica , Ribossomos/metabolismo , Transdução de Sinais
3.
Mol Ther ; 29(12): 3422-3435, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34371184

RESUMO

Mis-regulated epigenetic modifications in RNAs are associated with human cancers. The transfer RNAs (tRNAs) are the most heavily modified RNA species in cells; however, little is known about the functions of tRNA modifications in cancers. In this study, we uncovered that the expression levels of tRNA N7-methylguanosine (m7G) methyltransferase complex components methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) are significantly elevated in human lung cancer samples and negatively associated with patient prognosis. Impaired m7G tRNA modification upon METTL1/WDR4 depletion resulted in decreased cell proliferation, colony formation, cell invasion, and impaired tumorigenic capacities of lung cancer cells in vitro and in vivo. Moreover, gain-of-function and mutagenesis experiments revealed that METTL1 promoted lung cancer growth and invasion through regulation of m7G tRNA modifications. Profiling of tRNA methylation and mRNA translation revealed that highly translated mRNAs have higher frequencies of m7G tRNA-decoded codons, and knockdown of METTL1 resulted in decreased translation of mRNAs with higher frequencies of m7G tRNA codons, suggesting that tRNA modifications and codon usage play an essential function in mRNA translation regulation. Our data uncovered novel insights on mRNA translation regulation through tRNA modifications and the corresponding mRNA codon compositions in lung cancer, providing a new molecular basis underlying lung cancer progression.


Assuntos
Neoplasias Pulmonares , Biossíntese de Proteínas , Uso do Códon , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Humanos , Neoplasias Pulmonares/genética , Metiltransferases/genética , Metiltransferases/metabolismo , RNA de Transferência/genética
4.
Clin Genet ; 93(2): 374-377, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28617965

RESUMO

Microcephalic primordial dwarfisms are a group of rare Mendelian disorders characterized by severe growth retardation and microcephaly. The molecular basis is heterogeneous, with disease-causing genes implicated in different cellular functions. Recently, 2 patients were reported with the same homozygous variant in the WDR4 gene, coding for an enzyme responsible for the m7 G46 post transcriptional modification of tRNA. We report here 2 sisters harboring compound heterozygous variants of WDR4. Their phenotype differs from that of the first 2 described patients: they both have a severe microcephaly but only one of the 2 sisters had a head circumference at birth below -2 SD, their intellectual deficiency is less severe, and they have a growth hormone deficiency and a partial hypogonadotropic hypogonadotropism. One of the 2 variants is a frameshift mutation, and the other one is a missense occurring in the same nucleotide affected by the first reported pathogenic variant, which could therefore be a mutational hot spot. The description of these 2 sisters allow us to confirm that biallelic variants in the WDR4 gene can lead to a specific phenotype, characterized by severe growth retardation and microcephaly.


Assuntos
Nanismo/genética , Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Microcefalia/genética , Adolescente , Criança , Nanismo/fisiopatologia , Exoma/genética , Fácies , Feminino , Mutação da Fase de Leitura , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Microcefalia/fisiopatologia , Linhagem , Fenótipo , Irmãos
5.
J Adv Res ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38960276

RESUMO

INTRODUCTION: Growing interest toward RNA modification in cancer has inspired the exploration of gene sets related to multiple RNA modifications. However, a comprehensive elucidation of the clinical value of various RNA modifications in breast cancer is still lacking. OBJECTIVES: This study aimed to provide a strategy based on RNA modification-related genes for predicting therapy response and survival outcomes in breast cancer patients. METHODS: Genes related to thirteen RNA modification patterns were integrated for establishing a nine-gene-containing signature-RMscore. Alterations of tumor immune microenvironment and therapy response featured by different RMscore levels were assessed by bulk transcriptome, single-cell transcriptome and genomics analyses. The biological function of key RMscore-related molecules was investigated by cellular experiments in vitro and in vivo, using flow cytometry, immunohistochemistry and immunofluorescence staining. RESULTS: This study has raised an effective therapy strategy for breast cancer patients after a well-rounded investigation of RNA modification-related genes. With a great performance of predicting patient prognosis, high levels of the RMscore proposed in this study represented suppressive immune microenvironment and therapy resistance, including adjuvant chemotherapy and PD-L1 blockade treatment. As the key contributor of the RMscore, inhibition of WDR4 impaired breast cancer progression significantly in vitro and in vivo, as well as participated in regulating cell cycle and mTORC1 signaling pathway via m7G modification. CONCLUSION: Briefly, this study has developed promising and effective tactics to achieve the prediction of survival probabilities and treatment response in breast cancer patients.

6.
Cell Signal ; 118: 111145, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38493882

RESUMO

BACKGROUND: The N7-methylguanosine (m7G), a modification at defined internal positions within tRNAs and rRNAs, is correlated with tumor progression. Methyltransferase like 1 (METTL1)/ WD repeat domain 4 (WDR4) mediated tRNA m7G modification, which could alter many oncogenic mRNAs translation to promote progress of multiple cancer types. However, whether and how the internal mRNA m7G modification is involved in tumorigenesis remains unclear. METHODS: The immunohistochemistry assay was conducted to detect the expression of WDR4 and METTL1 in hepatocellular carcinoma (HCC) and the expression of both genes whether contributes to the prognosis of the survival rate of HCC patients. Then, CCK8, colony formation assays and tumor xenograft models were conducted to determine the effects of WDR4 on HCC cells in vitro and vivo. Besides, dot blot assay, m7G-MeRIP-seq and RNA-seq analysis were conducted to determine whether WDR4 contributes to m7G modification and underlying mechanism in HCC cells. Finally, rescue and CO-IP assay were conducted to explore whether WDR4 and METTL1 proteins form a complex in Huh7 cells. RESULTS: WDR4 modulates m7G modification at the internal sites of tumor-promoting mRNAs by forming the WDR4-METTL1 complex. WDR4 knockdown downregulated the expression of mRNA and protein levels of METTL1 gene and thus further modulate the formation of WDR4-METTL1 complex indirectly. METTL1 expression was markedly correlated with WDR4 expression in HCC tissues. HCC patients with high expression of both genes had a poor prognosis. CONCLUSIONS: WDR4 may contribute to HCC pathogenesis by interacting with and regulating the expression of METTL1 to synergistically modulate the m7G modification of target mRNAs in tumor cells.


Assuntos
Carcinoma Hepatocelular , Guanosina/análogos & derivados , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA Mensageiro/genética , Proteínas de Ligação ao GTP , Metiltransferases
7.
Exp Hematol Oncol ; 13(1): 8, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38268051

RESUMO

BACKGROUND: RNA modifications have been proven to play fundamental roles in regulating cellular biology process. Recently, maladjusted N7-methylguanosine (m7G) modification and its modifiers METTL1/WDR4 have been confirmed an oncogene role in multiple cancers. However, the functions and molecular mechanisms of METTL1/WDR4 in acute myeloid leukemia (AML) remain to be determined. METHODS: METTL1/WDR4 expression levels were quantified using qRT-PCR, western blot analysis on AML clinical samples, and bioinformatics analysis on publicly available AML datasets. CCK-8 assays and cell count assays were performed to determine cell proliferation. Flow cytometry assays were conducted to assess cell cycle and apoptosis rates. Multiple techniques were used for mechanism studies in vitro assays, such as northern blotting, liquid chromatography-coupled mass spectrometry (LC-MS/MS), tRNA stability analysis, transcriptome sequencing, small non-coding RNA sequencing, quantitative proteomics, and protein synthesis measurements. RESULTS: METTL1/WDR4 are significantly elevated in AML patients and associated with poor prognosis. METTL1 knockdown resulted in reduced cell proliferation and increased apoptosis in AML cells. Mechanically, METTL1 knockdown leads to significant decrease of m7G modification abundance on tRNA, which further destabilizes tRNAs and facilitates the biogenesis of tsRNAs in AML cells. In addition, profiling of nascent proteins revealed that METTL1 knockdown and transfection of total tRNAs that were isolated from METTL1 knockdown AML cells decreased global translation efficiency in AML cells. CONCLUSIONS: Taken together, our study demonstrates the important role of METTL1/WDR4 in AML leukaemogenesis, which provides a promising target candidate for AML therapy.

8.
BMC Med Genomics ; 16(1): 179, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37528384

RESUMO

N7 methylguanosine (m7G) has a crucial role the development of hepatocellular carcinoma (HCC). This study aimed to investigate the impact of the m7G methylation core genes (METTL1 and WDR4) and associated RNA risk signatures on HCC. we found m7G methylation core genes (METTL1 and WDR4) were upregulated in four HCC cell lines, and downregulation of METTL1 and WDR4 attenuated HCC cell proliferation, migration, and invasion. Moreover, METTL1 and WDR4 are upregulated in HCC tissues, and that there is a significant positive correlation between them. METTL1 and WDR4 were identified as independent prognostic markers for HCC by employing overall survival (OS), disease-specific survival (DSS), Progression Free Interval survival (PFI), and univariate/multivariate Cox analyses. We identified 1479 coding RNAs (mRNAs) and 232 long non-coding RNAs (lncRNAs) associated with METTL1 / WDR4 by using weighted coexpression network analysis (WGCNA) and co-clustering analysis. The least absolute shrinkage and selection operator (lasso) were used to constructing mRNA and lncRNA risk signatures associated with the METTL1 / WDR4. These risk were independent poor prognostic factors in HCC. Furthermore, we found that METTL1 / WDR4 expression and mRNA / lncRNA risk scores were closely associated with TP53 mutations. Clinicopathological features correlation results showed that METTL1 / WDR4 expression and mRNA / lncRNA risk score were associated with the stage and invasion depth (T) of HCC. To predict the overall survival of HCC individuals, we constructed a nomogram with METTL1/WDR4 expression, mRNA/lncRNA risk score, and clinicopathological features. In addition, we combined single-cell sequencing datasets and immune escape-related checkpoints to construct an immune escape-related protein-protein interaction(PPI) network. In conclusion, M7G methylated core genes (METTL1 and WDR4) and associated RNA risk signatures are associated with prognosis and immune escape in HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/genética , RNA Longo não Codificante/genética , Neoplasias Hepáticas/genética , Prognóstico , Linhagem Celular , Proteínas de Ligação ao GTP , Metiltransferases/genética
9.
J Cancer ; 14(8): 1293-1300, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37283791

RESUMO

Wilms tumor is the most common embryonal renal malignancy in children. WDR4 is an indispensable noncatalytic subunit of the RNA N7-methylguanosine (m7G) methyltransferase complex and plays an essential role in tumorigenesis. However, the relationship between polymorphisms in the WDR4 gene and susceptibility to Wilms tumor remains to be fully investigated. We performed a large case-control study involving 414 patients and 1199 cancer-free controls to investigate whether single nucleotide polymorphisms (SNPs) in the WDR4 gene are associated with Wilms tumor susceptibility. WDR4 gene polymorphisms (rs2156315 C > T, rs2156316 C > G, rs6586250 C > T, rs15736 G > A, and rs2248490 C > G) were genotyped using the TaqMan assay. In addition, unconditioned logistic regression analysis was performed, odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association between WDR4 gene SNPs and Wilms tumor susceptibility as well as the strength of the associations. We found that only the rs6586250 C>T polymorphism was significantly associated with an increased risk of Wilms tumor (adjusted OR=2.99, 95% CI = 1.28-6.97, P = 0.011 for the rs6586250 TT genotype; adjusted OR=3.08, 95% CI = 1.33-7.17, P = 0.009 for the rs6586250 CC/CT genotype). Furthermore, the stratification analysis revealed that patients with the rs6586250 TT genotype and carriers with 1-5 risk genotypes exhibited statistically significant associations with increased Wilms tumor risk in specific subgroups. However, the rs2156315 CT/TT genotype was identified as having a protective effect against Wilms tumor in the age >18 months subgroup compared with the rs2156315 CC genotype. In brief, our study demonstrated that the rs6586250 C > T polymorphism of the WDR4 gene was significantly associated with Wilms tumor. This finding may contribute to the understanding of the genetic mechanism of Wilms tumor.

10.
Cancer Lett ; 562: 216165, 2023 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-37028699

RESUMO

N7-methylguanosine (m7G) methylation, one of the most common RNA modifications in eukaryotes, has recently gained considerable attention. The biological functions of m7G modification in RNAs, including tRNA, rRNA, mRNA, and miRNA, remain largely unknown in human diseases. Owing to rapid advances in high-throughput technologies, increasing evidence suggests that m7G modification plays a critical role in cancer initiation and progression. As m7G modification and hallmarks of cancer are inextricably linked together, targeting m7G regulators may provide new possibilities for future cancer diagnoses and potential intervention targets. This review summarizes various detection methods for m7G modification, recent advances in m7G modification and tumor biology regarding their interplay and regulatory mechanisms. We conclude with an outlook on the future of diagnosing and treating m7G-related diseases.


Assuntos
MicroRNAs , Neoplasias , Humanos , Metilação , RNA Mensageiro/genética , RNA de Transferência/genética , RNA de Transferência/metabolismo , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia
11.
Mol Ther Nucleic Acids ; 31: 295-308, 2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36726408

RESUMO

In recent years, N7-methylguanosine (m7G) methylation, originally considered as messenger RNA (mRNA) 5' caps modifications, has been identified at defined internal positions within multiple types of RNAs, including transfer RNAs, ribosomal RNAs, miRNA, and mRNAs. Scientists have put substantial efforts to discover m7G methyltransferases and methylated sites in RNAs to unveil the essential roles of m7G modifications in the regulation of gene expression and determine the association of m7G dysregulation in various diseases, including neurological disorders. Here, we review recent findings regarding the distribution, abundance, biogenesis, modifiers, and functions of m7G modifications. We also provide an up-to-date summary of m7G detection and profile mapping techniques, databases for validated and predicted m7G RNA sites, and web servers for m7G methylation prediction. Furthermore, we discuss the pathological roles of METTL1/WDR-driven m7G methylation in neurological disorders. Last, we outline a roadmap for future directions and trends of m7G modification research, particularly in the central nervous system.

12.
Mol Ther Oncolytics ; 26: 27-34, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35784404

RESUMO

As one of the prevalent posttranscriptional modifications of RNA, N7-methylguanosine (m7G) plays essential roles in RNA processing, metabolism, and function, mainly regulated by the methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) complex. Emerging evidence suggests that the METTL1/WDR4 complex promoted or inhibited the processes of many tumors, including head and neck, lung, liver, colon, bladder cancer, and teratoma, dependent on close m7G methylation modification of tRNA or microRNA (miRNA). Therefore, METTL1 and m7G modification can be used as biomarkers or potential intervention targets, providing new possibilities for early diagnosis and treatment of tumors. This review will mainly focus on the mechanisms of METTL1/WDR4 via m7G in tumorigenesis and the corresponding detection methods.

13.
Trends Cell Biol ; 32(10): 819-824, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35907701

RESUMO

N7-methylguanosine (m7G) is a significant RNA modification occurring during epigenetic regulation. An increasing number of investigations have proved that the effect of m7G in suppressing cancer deserves more attention. Herein, we explore potential valuable targets based on present studies of m7G-related cancer to improve disease therapy and prognoses.


Assuntos
Epigênese Genética , Neoplasias , Guanosina/análogos & derivados , Humanos , Neoplasias/genética
14.
J Cancer ; 13(12): 3342-3347, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36186903

RESUMO

Hepatoblastoma, originating from hepatoblasts, is the most common hepatic malignancy. WD repeat domain 4 (WDR4) is a subunit of RNA N(7)-methylguanine (m7G) methyltransferase complex. Recently, WDR4 has shown oncogenic potential in various adult cancers, but its roles in pediatric cancers have not been reported. We performed a case-control study (313 cases vs. 1446 controls) to investigate whether genetic variants in the WDR4 gene influence hepatoblastoma susceptibility in the Chinese Han nationality. We first determine the genotypes of five WDR4 gene polymorphisms (rs2156315 C>T, rs2156316 C>G, rs6586250 C>T, rs15736 G>A, rs2248490 C>G) in participants, using the Taqman assay. And then, an unconditional logistic regression analysis was performed to assess the association between WDR4 gene polymorphisms and hepatoblastoma risk. Overall, we did not find any polymorphism significantly associated with the risk of developing hepatoblastoma. Instead, the stratified analysis revealed that the co-existence of 2-5 risk genotypes increased hepatoblastoma risk by 2.23 folds in girls (adjusted odds ratio=2.23, 95% confidence interval=1.17-4.23, P=0.014). In conclusion, our results demonstrate that single selected polymorphisms were too weak to exert a significant effect on the whole study population. However, in combination, two or more WDR4 gene polymorphisms significantly conferred increased hepatoblastoma risk in girls. Our findings may encourage more genetic association studies to discover significant polymorphisms in the WDR4 gene for hepatoblastoma.

15.
Cancer Commun (Lond) ; 42(3): 223-244, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35179319

RESUMO

BACKGROUND: Cancer cells selectively promote the translation of oncogenic transcripts to stimulate cancer progression. Although growing evidence has revealed that tRNA modifications and related genes participate in this process, their roles in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized. Here, we sought to investigate the function and mechanisms of the transfer RNA (tRNA) N7-methylguanosine (m7 G) modification in regulating the occurrence and development of HNSCC. METHODS: Cell lost-of-function and gain-of-function assays, xenograft models, conditional knockout and knockin mouse models were used to study the physiological functions of tRNA m7 G modification in HNSCC tumorigenesis. tRNA modification and expression profiling, mRNA translation profiling and rescue assays were performed to uncover the underlying molecular mechanisms. Single-cell RNA sequencing (scRNA-seq) was conducted to explore the tumor microenvironment changes. RESULTS: The tRNA m7 G methyltransferase complex components Methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4) were upregulated in HNSCC and associated with a poor prognosis. Functionally, METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models. Mechanistically, ablation of METTL1 reduced the m7 G levels of 16 tRNAs, inhibiting the translation of a subset of oncogenic transcripts, including genes related to the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In addition, chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettl1 in mouse HNSCC. Furthermore, scRNA-seq results revealed that Mettl1 knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment. CONCLUSIONS: The tRNA m7 G methyltransferase METTL1 was found to promote the development and malignancy of HNSCC through regulating global mRNA translation, including the PI3K/AKT/mTOR signaling pathway, and found to alter immune landscape. METTL1 could be a promising treatment target for HNSCC patients.


Assuntos
Neoplasias de Cabeça e Pescoço , Proteínas Proto-Oncogênicas c-akt , Animais , Carcinogênese/genética , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Guanosina/análogos & derivados , Neoplasias de Cabeça e Pescoço/genética , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Metiltransferases/efeitos adversos , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA de Transferência/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral
16.
J Pers Med ; 11(8)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34442404

RESUMO

Infertility is one of the important problems in the modern world. Male infertility is characterized by several clinical manifestations, including low sperm production (oligozoospermia), reduced sperm motility (asthenozoospermia), and abnormal sperm morphology (teratozoospermia). WDR4, known as Wuho, controls fertility in Drosophila. However, it is unclear whether WDR4 is associated with clinical manifestations of male fertility in human. Here, we attempted to determine the physiological functions of WDR4 gene. Two cohorts were applied to address this question. The first cohort was the general population from Taiwan Biobank. Genomic profiles from 68,948 individuals and 87 common physiological traits were applied for phenome-wide association studies (PheWAS). The second cohort comprised patients with male infertility from Wan Fang Hospital, Taipei Medical University. In total, 81 male participants were recruited for the genetic association study. Clinical records including gender, age, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total sperm number, sperm motility, and sperm morphology were collected. In the first cohort, results from PheWAS exhibited no associations between WDR4 genetic variants and 87 common physiological traits. In the second cohort, a total of four tagging single-nucleotide polymorphisms (tSNPs) from WDR4 gene (rs2298666, rs465663, rs2248490, and rs3746939) were selected for genotyping. We found that SNP rs465663 solely associated with asthenozoospermia. Functional annotations through the GTEx portal revealed the correlation between TT or TC genotype and low expression of WDR4. Furthermore, we used mouse embryonic fibroblasts cells from mwdr4 heterozygous (+/‒) mice for functional validation by western blotting. Indeed, low expression of WDR4 contributed to ROS-induced DNA fragmentation. In conclusion, our results suggest a critical role of WDR4 gene variant as well as protein expression in asthenozoospermia.

17.
Aging (Albany NY) ; 13(14): 18360-18375, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282052

RESUMO

Recent publications have presented research showing that WD repeat domain 4 (WDR4) plays a significant role in various kinds of malignant tumours. However, the expression profile of WDR4 is still unspecified, as is its significance in the analysis of human pan-cancer. We conducted an in-depth analysis of three aspects of WDR4 expression patterns from 33 types of cancer and determined the value of WDR4 for prognostic prediction and carcinoma drug resistance prediction. WDR4 was expressed in different cancer cell lines at inconsistent levels. Aberrant expression of WDR4 has been observed in various malignant cancers and is significantly implicated in overall survival outcomes. The expression level of WDR4 is also strongly associated with tumour immunity, such as immune scores and tumour-infiltrating immune cells. The level of WDR4 is related to microsatellite instability and tumour mutation burden in several types of malignancy, and validation studies implied that WDR4-associated terms and pathways are involved in malignancy. We explored the expression level of WDR4 across 33 types of cancer and showed that WDR4 plays a significant role during cancer development. More crucially, WDR4 is associated with immune infiltration, which suggests that WDR4 could be an immunotherapy target in cancers. In summary, our research showed that WDR4 plays a vital role in tumorigenesis and has the potential for to be targeted with treatments.


Assuntos
Biomarcadores Tumorais , Proteínas de Ligação ao GTP/genética , Imunidade , Neoplasias/genética , Neoplasias/imunologia , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Imunomodulação , Instabilidade de Microssatélites , Mutação , Neoplasias/patologia , Prognóstico , Análise de Sobrevida , Microambiente Tumoral
18.
Eur J Med Genet ; 61(8): 468-472, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29597095

RESUMO

Primordial dwarfism (PD) is mainly characterized by growth deficiency with heterogeneous phenotypes. A group of genes are known to be associated with PD or PD-related syndrome. WD repeat domain 4 (WDR4) is recently reported to be responsible for PD. Here we report a 6-year-old boy from a non-consanguineous couple with motor and speech delay as well as intellectual disability. Whole exome sequencing (WES) identified a missense mutation (NM_033661.4:c.491A > C; p.(Asp164Ala)) and a small insertion (NM_033661.4:c.940dupC; p.(Leu314Profs*16)) of WDR4 in this patient. Two novel mutations confirmed by Sanger sequencing are from father and mother respectively according to a recessive inheritance pattern. Asp164Ala located in functional region is predicted to be deleterious by two kinds of algorithm. The small insertion causing a frameshift mutation leads to truncated protein. In this study, we present two novel WDR4 mutations responsible for PD in a 6-year-old patient, expanding the molecular and phenotype spectrum of WDR4-related PD.


Assuntos
Nanismo/genética , Proteínas de Ligação ao GTP/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Fenótipo , Criança , Nanismo/patologia , Mutação da Fase de Leitura , Humanos , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Mutação de Sentido Incorreto , Síndrome
19.
Mol Cell Oncol ; 4(6): e1364212, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29209651

RESUMO

The tumor suppressive functions of promyelocytic leukemia (PML) have been attributed mainly to its inhibition of various malignant properties of tumor cells. Our recent work identifies a PML ubiquitination and degradation pathway, which regulates both cell and non-cell components of the tumor microenvironment, thereby potentiating immune evasion and metastasis.

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