Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.136
Filtrar
1.
Viruses ; 14(12)2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36560714

RESUMO

The spliceosome is a massive ribonucleoprotein structure composed of five small nuclear ribonucleoprotein (snRNP) complexes that catalyze the removal of introns from pre-mature RNA during constitutive and alternative splicing. EFTUD2, PRPF8, and SNRNP200 are core components of the U5 snRNP, which is crucial for spliceosome function as it coordinates and performs the last steps of the splicing reaction. Several studies have demonstrated U5 snRNP proteins as targeted during viral infection, with a limited understanding of their involvement in virus-host interactions. In the present study, we deciphered the respective impact of EFTUD2, PRPF8, and SNRNP200 on viral replication using mammalian reovirus as a model. Using a combination of RNA silencing, real-time cell analysis, cell death and viral replication assays, we discovered distinct and partially overlapping novel roles for EFTUD2, PRPF8, and SNRNP200 in cell survival, apoptosis, necroptosis, and the induction of the interferon response pathway. For instance, we demonstrated that EFTUD2 and SNRNP200 are required for both apoptosis and necroptosis, whereas EFTUD2 and PRPF8 are required for optimal interferon response against viral infection. Moreover, we demonstrated that EFTUD2 restricts viral replication, both in a single cycle and multiple cycles of viral replication. Altogether, these results establish U5 snRNP core components as key elements of the cellular antiviral response.


Assuntos
Ribonucleoproteína Nuclear Pequena U5 , Viroses , Animais , Ribonucleoproteína Nuclear Pequena U5/química , Ribonucleoproteína Nuclear Pequena U5/genética , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Proteínas Centrais de snRNP/genética , Proteínas Centrais de snRNP/metabolismo , Interferons/metabolismo , Splicing de RNA , Apoptose , Mamíferos
2.
Front Immunol ; 13: 1037318, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405716

RESUMO

Background: Alzheimer's disease is the most common neurodegenerative disease worldwide. Metabolic syndrome is the most common metabolic and endocrine disease in the elderly. Some studies have suggested a possible association between MetS and AD, but few studied genes that have a co-diagnostic role in both diseases. Methods: The microarray data of AD (GSE63060 and GSE63061 were merged after the batch effect was removed) and MetS (GSE98895) in the GEO database were downloaded. The WGCNA was used to identify the co-expression modules related to AD and MetS. RF and LASSO were used to identify the candidate genes. Machine learning XGBoost improves the diagnostic effect of hub gene in AD and MetS. The CIBERSORT algorithm was performed to assess immune cell infiltration MetS and AD samples and to investigate the relationship between biomarkers and infiltrating immune cells. The peripheral blood mononuclear cells (PBMCs) single-cell RNA (scRNA) sequencing data from patients with AD and normal individuals were visualized with the Seurat standard flow dimension reduction clustering the metabolic pathway activity changes each cell with ssGSEA. Results: The brown module was identified as the significant module with AD and MetS. GO analysis of shared genes showed that intracellular transport and establishment of localization in cell and organelle organization were enriched in the pathophysiology of AD and MetS. By using RF and Lasso learning methods, we finally obtained eight diagnostic genes, namely ARHGAP4, SNRPG, UQCRB, PSMA3, DPM1, MED6, RPL36AL and RPS27A. Their AUC were all greater than 0.7. Higher immune cell infiltrations expressions were found in the two diseases and were positively linked to the characteristic genes. The scRNA-seq datasets finally obtained seven cell clusters. Seven major cell types including CD8 T cell, monocytes, T cells, NK cell, B cells, dendritic cells and macrophages were clustered according to immune cell markers. The ssGSEA revealed that immune-related gene (SNRPG) was significantly regulated in the glycolysis-metabolic pathway. Conclusion: We identified genes with common diagnostic effects on both MetS and AD, and found genes involved in multiple metabolic pathways associated with various immune cells.


Assuntos
Doença de Alzheimer , Síndrome Metabólica , Doenças Neurodegenerativas , Humanos , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Síndrome Metabólica/genética , Leucócitos Mononucleares/metabolismo , Algoritmos , Aprendizado de Máquina , Biomarcadores , Proteínas Centrais de snRNP
3.
BMC Genomics ; 23(1): 744, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36348279

RESUMO

BACKGROUND: Alternative splicing (AS) is an important channel for gene expression regulation and protein diversification, in addition to a major reason for the considerable differences in the number of genes and proteins in eukaryotes. In plants, U2 small nuclear ribonucleoprotein B″ (U2B″), a component of splicing complex U2 snRNP, plays an important role in AS. Currently, few studies have investigated plant U2B″, and its mechanism remains unclear. RESULT: Phylogenetic analysis, including gene and protein structures, revealed that U2B″ is highly conserved in plants and typically contains two RNA recognition motifs. Subcellular localisation showed that OsU2B″ is located in the nucleus and cytoplasm, indicating that it has broad functions throughout the cell. Elemental analysis of the promoter region showed that it responded to numerous external stimuli, including hormones, stress, and light. Subsequent qPCR experiments examining response to stress (cold, salt, drought, and heavy metal cadmium) corroborated the findings. The prediction results of protein-protein interactions showed that its function is largely through a single pathway, mainly through interaction with snRNP proteins. CONCLUSION: U2B″ is highly conserved in the plant kingdom, functions in the nucleus and cytoplasm, and participates in a wide range of processes in plant growth and development.


Assuntos
Ribonucleoproteína Nuclear Pequena U2 , Spliceossomos , Proteínas Centrais de snRNP/genética , Ribonucleoproteína Nuclear Pequena U2/química , Ribonucleoproteína Nuclear Pequena U2/genética , Ribonucleoproteína Nuclear Pequena U2/metabolismo , Filogenia , Sequência de Aminoácidos , RNA Nuclear Pequeno/genética , Splicing de RNA
4.
Hereditas ; 159(1): 38, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36195955

RESUMO

BACKGROUND: The prevalence of Alzheimer's disease (AD) varies based on gender. Due to the lack of early stage biomarkers, most of them are diagnosed at the terminal stage. This study aimed to explore sex-specific signaling pathways and identify diagnostic biomarkers of AD. METHODS: Microarray dataset for blood was obtained from the Gene Expression Omnibus (GEO) database of GSE63060 to conduct differentially expressed genes (DEGs) analysis by R software limma. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene set enrichment analysis (GSEA) were conducted. Immune checkpoint gene expression was compared between females and males. Using CytoHubba, we identified hub genes in a protein-protein interaction network (PPI). Then, we evaluated their distinct effectiveness using unsupervised hierarchical clustering. Support vector machine (SVM) and ten-fold cross-validation were used to further verify these biomarkers. Lastly, we confirmed our findings by using another independent dataset. RESULTS: A total of 37 female-specific DEGs and 27 male-specific DEGs were identified from GSE63060 datasets. Analyses of enrichment showed that female-specific DEGs primarily focused on energy metabolism, while male-specific DEGs mostly involved in immune regulation. Three immune-checkpoint-relevant genes dysregulated in males. In females, however, these eight genes were not differentially expressed. SNRPG, RPS27A, COX7A2, ATP5PO, LSM3, COX7C, PFDN5, HINT1, PSMA6, RPS3A and RPL31 were regarded as hub genes for females, while SNRPG, RPL31, COX7C, RPS27A, RPL35A, RPS3A, RPS20 and PFDN5 were regarded as hub genes for males. Thirteen hub genes mentioned above was significantly lower in both AD and mild cognitive impairment (MCI). The diagnostic model of 15-marker panel (13 hub genes with sex and age) was developed. Both the training dataset and the independent validation dataset have area under the curve (AUC) with a high value (0.919, 95%CI 0.901-0.929 and 0.803, 95%CI 0.789-0.826). Based on GSEA for hub genes, they were associated with some aspects of AD pathogenesis. CONCLUSION: DEGs in males and females contribute differently to AD pathogenesis. Algorithms combining blood-based biomarkers may improve AD diagnostic accuracy, but large validation studies are needed.


Assuntos
Doença de Alzheimer , Biologia Computacional , Algoritmos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Biomarcadores/metabolismo , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Proteínas do Tecido Nervoso , Caracteres Sexuais , Máquina de Vetores de Suporte , Proteínas Centrais de snRNP
5.
Cryobiology ; 108: 51-56, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35926569

RESUMO

DNA methylation alters gene expression in numerous biological processes, including embryonic development. It is little known about the effect of cryopreservation on sperm DNA methylation. The present study has investigated whether cryopreservation causes abnormal DNA methylation in cynomolgus macaque sperm for five critical genes that includes the maternally imprinted gene (SNRPN), genes associated with male infertility (HSPA1L, MTHFR) and genes involved in embryonic development (TET3, LZTR1). Our results showed that sperm motility, the percentage of acrosomal integrity, DNA integrity and mitochondrial membrane potential were decreased after cryopreservation either being frozen with penetrating cryoprotectant, glycerol (Gly) or ethylene glycol (EG), compared to fresh sperm (p = 0.000), but the methylation patterns of the five target genes from cynomolgus macaque sperm samples were not affected after cryopreservation as evaluated by the Bisulfite Sequencing PCR (BSP) method. The data indicates that the current protocol for sperm cryopreservation of cynomolgus macaque is safe in terms of DNA methylation levels in these genes related to critical sperm functions.


Assuntos
Criopreservação , Preservação do Sêmen , Animais , Criopreservação/métodos , Metilação de DNA , Desenvolvimento Embrionário , Etilenoglicol , Feminino , Fertilização , Glicerol , Macaca fascicularis/genética , Masculino , Gravidez , Sêmen , Preservação do Sêmen/métodos , Preservação do Sêmen/veterinária , Motilidade Espermática/genética , Espermatozoides , Proteínas Centrais de snRNP
6.
Hum Mutat ; 43(11): 1567-1575, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35842787

RESUMO

Prader-Willi syndrome (PWS; MIM# 176270) is a neurodevelopmental disorder caused by the loss of expression of paternally imprinted genes within the PWS region located on 15q11.2. It is usually caused by either maternal uniparental disomy of chromosome 15 (UPD15) or 15q11.2 recurrent deletion(s). Here, we report a healthy carrier of a balanced X;15 translocation and her two daughters, both with the karyotype 45,X,der(X)t(X;15)(p22;q11.2),-15. Both daughters display symptoms consistent with haploinsufficiency of the SHOX gene and PWS. We explored the architecture of the derivative chromosomes and investigated effects on gene expression in patient-derived neural cells. First, a multiplex ligation-dependent probe amplification methylation assay was used to determine the methylation status of the PWS-region revealing maternal UPD15 in daughter 2, explaining her clinical symptoms. Next, short read whole genome sequencing and 10X genomics linked read sequencing was used to pinpoint the exact breakpoints of the translocation. Finally, we performed transcriptome sequencing on neuroepithelial stem cells from the mother and from daughter 1 and observed biallelic expression of genes in the PWS region (including SNRPN) in daughter 1. In summary, our multi-omics analysis highlights two different PWS mechanisms in one family and provide an example of how structural variation can affect imprinting through long-range interactions.


Assuntos
Metilação de DNA , Síndrome de Prader-Willi , Cromossomos Humanos Par 15/genética , Feminino , Impressão Genômica , Humanos , Síndrome de Prader-Willi/genética , Translocação Genética , Dissomia Uniparental/genética , Proteínas Centrais de snRNP/genética
7.
Mol Reprod Dev ; 89(7): 290-297, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35698757

RESUMO

Imprinted genes are inherited with different DNA methylation patterns depending on the maternal or paternal origin of the allele. In cattle (Bos taurus), abnormal methylation of these genes is linked to the large offspring syndrome, a neonatal overgrowth phenotype analogous to the human Beckwith-Wiedemann syndrome. We hypothesized that in bovine oocytes, some of the methylation patterns on maternally imprinted genes are acquired in the last phase of folliculogenesis. The pyrosequencing analysis of IGF2R, KCNQ1, PLAGL1, and SNRPN imprinted genes showed no clear progression of methylation in oocytes from follicles 1-2 mm (late pre antral/early antral) and up. Instead, these oocytes displayed complete methylation at the imprinted differentially methylated regions (>80%). Other mechanisms related to imprint maintenance should be investigated to explain the hypomethylation at IGF2R, KCNQ1, PLAGL1, and SNRPN maternally imprinted sites observed in some bovine embryos.


Assuntos
Metilação de DNA , Impressão Genômica , Animais , Bovinos , Proteínas de Ciclo Celular , Humanos , Canal de Potássio KCNQ1/genética , Oogênese , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Proteínas Centrais de snRNP/genética
8.
Zygote ; 30(5): 638-647, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35603594

RESUMO

High rates of infertility in type 2 diabetic (T2DM) men have led to attempts to understand the mechanisms involved in this process. This condition can be investigated from at least two aspects, namely sperm quality indices and epigenetic alterations. Epigenetics science encompasses the phenomena that can lead to inherited changes independently of the genetics. This study has been performed to test the hypothesis of the relationship between T2DM and the epigenetic profile of the sperm, as well as sperm quality indices. This research included 42 individuals referred to the infertility clinic of Royan Institute, Iran in 2019-2021. The study subjects were assigned to three groups: normozoospermic non-diabetic (control), normozoospermic diabetic (DN) and non-normozoospermic diabetic (D.Non-N). Sperm DNA fragmentation was evaluated using the sperm chromatin structure assay technique. The global methylation level was examined using 5-methyl cytosine antibody and the methylation status in differentially methylated regions of H19, MEST, and SNRPN was assessed using the methylation-sensitive high-resolution melting technique. The results showed that the sperm global methylation in spermatozoa of D.Non-N group was significantly reduced compared with the other two groups (P < 0.05). The MEST and H19 genes were hypomethylated in the spermatozoa of D.Non-N individuals, but the difference level was not significant for MEST. The SNRPN gene was significantly hypermethylated in these individuals (P < 0.05). The results of this study suggest that T2DM alters the methylation profile and epigenetic programming in spermatozoa of humans and that these methylation changes may ultimately influence the fertility status of men with diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Impressão Genômica , Cromatina/metabolismo , Citosina/metabolismo , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Masculino , Sêmen/metabolismo , Espermatozoides/metabolismo , Proteínas Centrais de snRNP/genética , Proteínas Centrais de snRNP/metabolismo
9.
Dis Model Mech ; 15(6)2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35593225

RESUMO

Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for cerebrocostomandibular syndrome (CCMS). We show that Snrpb heterozygous mouse embryos arrest shortly after implantation. Additionally, heterozygous deletion of Snrpb in the developing brain and neural crest cells models craniofacial malformations found in CCMS, and results in death shortly after birth. RNAseq analysis of mutant heads prior to morphological defects revealed increased exon skipping and intron retention in association with increased 5' splice site strength. We found increased exon skipping in negative regulators of the P53 pathway, along with increased levels of nuclear P53 and P53 target genes. However, removing Trp53 in Snrpb heterozygous mutant neural crest cells did not completely rescue craniofacial development. We also found a small but significant increase in exon skipping of several transcripts required for head and midface development, including Smad2 and Rere. Furthermore, mutant embryos exhibited ectopic or missing expression of Fgf8 and Shh, which are required to coordinate face and brain development. Thus, we propose that mis-splicing of transcripts that regulate P53 activity and craniofacial-specific genes contributes to craniofacial malformations. This article has an associated First Person interview with the first author of the paper.


Assuntos
Anormalidades Craniofaciais , Micrognatismo , Animais , Anormalidades Craniofaciais/genética , Humanos , Deficiência Intelectual , Camundongos , Micrognatismo/genética , Morfogênese , Crista Neural , Costelas/anormalidades , Proteína Supressora de Tumor p53/genética , Proteínas Centrais de snRNP
10.
Eur J Med Genet ; 65(4): 104456, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35218942

RESUMO

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternally-inherited UBE3A on chromosome 15q11.2. In AS due to a chromosomal deletion that encompasses UBE3A, paternal uniparental disomy of chromosome 15, or imprinting defects (ImpD), the SNRPN locus is unmethylated, while in neurotypical individuals, it is ∼50% methylated. We present the developmental profile of two adults with mild AS assessed using standardized behavioral and neurodevelopmental measures. Both had intellectual disability with unusually advanced verbal communication skills compared to other individuals with AS. Methylation of the SNRPN locus was examined using Methylation Specific Quantitative Melt Analysis (MS-QMA) in different tissues at one time point for participant A (22 years) and two time points for participant B (T1: 22 years, T2: 25 years), and these levels were compared to a typical AS cohort. While participant A showed methylation levels comparable to the typical AS cohort, participant B showed methylation mosaicism in all tissues at both time points and changes in methylation levels from T1 to T2. AS should be considered in individuals with intellectual disability and verbal speech who may not have the typical symptoms of AS.


Assuntos
Síndrome de Angelman , Adulto , Síndrome de Angelman/genética , Cromossomos Humanos Par 15/genética , Metilação de DNA , Impressão Genômica , Humanos , Mosaicismo , Dissomia Uniparental , Proteínas Centrais de snRNP/genética
11.
Zhonghua Gan Zang Bing Za Zhi ; 30(1): 63-68, 2022 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-35152671

RESUMO

Objective: To study the expression and effect of small nuclear ribonucleoprotein-associated protein B (SNRPB) on proliferation and metastasis of liver cancer tissues and cells. Methods: The bioinformatics database starBase v3.0 and GEPIA were used to analyze the expression of SNRPB in liver cancer tissue and normal liver tissue, as well as the survival and prognosis of liver cancer patients. The expression of SNRPB mRNA and protein in liver cancer cell lines were analyzed by qRT-PCR and Western blot. RNA interference technique (siRNA) was used to determine SNRPB protein expression down-regulation. The proliferation effect on hepatocellular carcinoma cells was observed by MTT assay. Transwell invasion and migration assay was used to detect the changes in the metastatic ability of liver cancer cells after SNRPB down-regulation. Western blot was used to detect the changes of epithelial mesenchymal transition (EMT) markers in liver cancer cells after down-regulation of SNRPB expression. Data were compared between two groups and multiple groups using t-test and analysis of variance. Results: The expression of SNRPB was significantly higher in liver cancer tissue than normal liver tissue, and its expression level was correlated with the prognosis of liver cancer patients. Compared with the immortalized hepatocyte LO(2), the expression of SNRPB was significantly increased in the liver cancer cells (P < 0.01). siRNA-SNRPB had significantly inhibited the expression of SNRPB mRNA and protein in liver cancer cells. MTT results showed that the absorbance value was lower in SNRPB knockdown group than negative control group, and the difference at 96 h after transfection was most significant (P < 0.01). Transwell assay results showed that compared with the negative control group, the SNRPB knockdown group (MHCC-97H: 121.27 ± 8.12 vs. 46.38 ± 7.54; Huh7: 126.50 ± 6.98 vs. 41.10 ± 8.01) invasion and migration (MHCC-97H: 125.20 ± 4.77 vs. 43.18 ± 7.32; Huh7: 132.22 ± 8.21 vs. 38.00 ± 6.78) ability was significantly reduced (P < 0.01) in liver cancer cells. Western blot showed that the expression level of epithelial phenotype marker E-cadherin was decreased after down-regulation of SNRPB, while the expression levels of mesenchymal phenotype markers N-cadherin and vimentin was increased, suggesting that down-regulation of SNRPB inhibited EMT in liver cancer cells. Conclusion: SNRPB expression is significantly increased in liver cancer tissues and cells, and it is involved in regulating the proliferation, metastasis and EMT of liver cancer cells.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Proteínas Centrais de snRNP
12.
Elife ; 112022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34984976

RESUMO

Protein arginine methyltransferases (PRMTs) are required for the regulation of RNA processing factors. Type I PRMT enzymes catalyze mono- and asymmetric dimethylation; Type II enzymes catalyze mono- and symmetric dimethylation. To understand the specific mechanisms of PRMT activity in splicing regulation, we inhibited Type I and II PRMTs and probed their transcriptomic consequences. Using the newly developed Splicing Kinetics and Transcript Elongation Rates by Sequencing (SKaTER-seq) method, analysis of co-transcriptional splicing demonstrated that PRMT inhibition resulted in altered splicing rates. Surprisingly, co-transcriptional splicing kinetics did not correlate with final changes in splicing of polyadenylated RNA. This was particularly true for retained introns (RI). By using actinomycin D to inhibit ongoing transcription, we determined that PRMTs post-transcriptionally regulate RI. Subsequent proteomic analysis of both PRMT-inhibited chromatin and chromatin-associated polyadenylated RNA identified altered binding of many proteins, including the Type I substrate, CHTOP, and the Type II substrate, SmB. Targeted mutagenesis of all methylarginine sites in SmD3, SmB, and SmD1 recapitulated splicing changes seen with Type II PRMT inhibition, without disrupting snRNP assembly. Similarly, mutagenesis of all methylarginine sites in CHTOP recapitulated the splicing changes seen with Type I PRMT inhibition. Examination of subcellular fractions further revealed that RI were enriched in the nucleoplasm and chromatin. Taken together, these data demonstrate that, through Sm and CHTOP arginine methylation, PRMTs regulate the post-transcriptional processing of nuclear, detained introns.


Assuntos
Regulação da Expressão Gênica , Íntrons/genética , Proteínas Nucleares/genética , Proteína-Arginina N-Metiltransferases/genética , Fatores de Transcrição/genética , Proteínas Centrais de snRNP/genética , Linhagem Celular , Humanos , Metilação , Proteínas Nucleares/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Centrais de snRNP/metabolismo
13.
J Psychiatr Res ; 147: 39-49, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35016150

RESUMO

Schizophrenia (SCZ) is a highly heritable, polygenic complex mental disorder with imprecise diagnostic boundaries. Finding sensitive and specific novel biomarkers to improve the biological homogeneity of SCZ diagnosis is still one of the research hotspots. To identify the blood specific diagnostic biomarkers of SCZ, we performed RNA sequencing (RNA-seq) on 30 peripheral blood samples from 15 first-episode drug-naïve SCZ patients and 15 healthy controls (CTL). By performing multiple bioinformatics analysis algorithms based on RNA-seq data and microarray datasets, including differential expression genes (DEGs) analysis, WGCNA and CIBERSORT, we first identified 6 specific key genes (TOMM7, SNRPG, KRT1, AQP10, TMEM14B and CLEC12A) in SCZ. Moreover, we found that the proportions of lymphocyte, monocyte and neutrophils were significantly distinct in SCZ patients with CTL samples. Therefore, combining various features including age, sex and the novel blood biomarkers, we constructed the risk prediction model with three classifiers (RF: Random Forest; SVM: support vector machine; DT: decision tree) through repeated k-fold cross validation ensuring better generalizability. Finest result of Area under Receiver Operating Characteristic (AUROC) score of 0.91 was achieved by RF classifier and with a comparable good performance of AUROC 0.77 in external validation dataset. A lower AUROC of 0.63 was demonstrated when it was further applied to a Bipolar disorder (BPD) cohort. In conclusion, the study identified three peripheral core immunocytes and six key genes associated with the occurrence of SCZ, and further studies are required to test and validate these novel biomarkers for early diagnosis and treatment of SCZ.


Assuntos
Transtorno Bipolar , Esquizofrenia , Biomarcadores , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/genética , Diagnóstico Precoce , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Receptores Mitogênicos/genética , Receptores Mitogênicos/metabolismo , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Análise de Sequência de RNA , Proteínas Centrais de snRNP/genética
14.
J Med Genet ; 59(7): 719-722, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099539

RESUMO

BACKGROUND: Prader-Willi syndrome (PWS) is an imprinting disorder caused by the absence of paternal expressed genes in the Prader-Willi critical region (PWCR) on chromosome 15q11.2-q13. Three molecular mechanisms have been known to cause PWS, including a deletion in the PWCR, uniparental disomy 15 and imprinting defects. RESULTS: We report the first case of PWS associated with a single-nucleotide SNRPN variant in a 10-year-old girl presenting with clinical features consistent with PWS, including infantile hypotonia and feeding difficulty, developmental delay with cognitive impairment, excessive eating with central obesity, sleep disturbances, skin picking and related behaviour issues. Whole-exome sequencing revealed a de novo mosaic nonsense variant of the SNRPN gene (c.73C>T, p.R25X) in 10% of DNA isolated from buccal cells and 19% of DNA from patient-derived lymphoblast cells. DNA methylation study did not detect an abnormal methylation pattern in the SNRPN locus. Parental origin studies showed a paternal source of an intronic single-nucleotide polymorphism within the locus in proximity to the SNRPN variant. CONCLUSIONS: This is the first report that provides evidence of a de novo point mutation of paternal origin in SNRPN as a new disease-causing mechanism for PWS. This finding suggests that gene sequencing should be considered as part of the diagnostic workup in patients with clinical suspicion of PWS.


Assuntos
Síndrome de Prader-Willi , Criança , Feminino , Humanos , Cromossomos Humanos Par 15/genética , DNA , Metilação de DNA/genética , Impressão Genômica , Mucosa Bucal , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Proteínas Centrais de snRNP/genética , Polimorfismo de Nucleotídeo Único
15.
Ann Hum Genet ; 86(2): 71-79, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34779508

RESUMO

Angelman syndrome (AS) (OMIM#105830) is an imprinting disorder caused due to alterations in the maternal chr 15q11-13 region. Majority of cases can be diagnosed by methylation-specific polymerase chain reaction (MS-PCR) of SNRPN gene and by UBE3A sequencing, however, about 10% of cases with AS phenotype remain undiagnosed. Differential diagnoses of AS can be detected by chromosomal microarray (CMA) and clinical exome sequencing (CES). In this study, 30 cases with AS features were evaluated by MS-PCR, CMA, and CES. SNRPN MS-PCR confirmed AS in eight (26%), CMA and CES diagnosed nine (30%) cases. One case was identified with a novel variant c.1125C > T in GABRG3, located at 15q12 region, which is currently not associated with any syndrome. The GABRG3 gene is also speculated to be imprinted, a MS-PCR assay was designed to confirm its differential parental methylation status. This assay identified another case with altered GABRG3 methylation. The two cases with GABRG3 alteration-sequence change and methylation indicate that GABRG3 may be associated with a subtype of AS or a new related syndrome. Performing GABRG3 MS-PCR and sequencing of a larger group of patients with AS phenotype and normal SNPRN and UBE3A status will help in establishing exact genotype-phenotype correlation.


Assuntos
Síndrome de Angelman , Receptores de GABA-A , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Metilação de DNA , Impressão Genômica , Humanos , Fenótipo , Receptores de GABA-A/genética , Proteínas Centrais de snRNP/genética
16.
Genes (Basel) ; 12(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200226

RESUMO

Prader-Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader-Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the 'Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations' (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype-phenotype relationship in PWS.


Assuntos
Proteínas Nucleares/genética , Síndrome de Prader-Willi/genética , Proteínas Centrais de snRNP/genética , Células Cultivadas , Feminino , Impressão Genômica , Células HEK293 , Homozigoto , Humanos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Proteínas Nucleares/metabolismo , Fenótipo , Síndrome de Prader-Willi/diagnóstico , Proteínas Centrais de snRNP/metabolismo
17.
Genet Test Mol Biomarkers ; 25(5): 334-345, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33970702

RESUMO

Background: Vascular endothelial growth factors (VEGFs) are important for glioblastoma multiforme (GBM) growth and development. However, the effects of VEGF-targeting drugs in primary GBM remain poorly understood. Aim: We aimed to explore the key genes correlated with VEGF expression and prognosis and elucidate their potential implications in GBM anti-VEGF therapy. Materials and Methods: RNA-seq data with the corresponding clinicopathological information was retrieved from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas. Weighted gene coexpression network analyses was performed on differentially expressed genes to construct coexpression modules and investigate their correlation with VEGFs. Functional enrichment analyses were performed based on the coexpressed genes from the most promising modules. CytoHubba and Kaplan-Meier analyses were implemented to identify the key genes in the modules of interest. The oncomine database, quantitative reverse transcription PCR, and the Human Protein Atlas were used to investigate the expression characteristics of the identified key genes. Results: Four modules (cyan, green, purple, and tan) correlated significantly with VEGF expression. Enrichment analyses suggested that extracellular matrix-receptor interaction, growth factor binding, and the PI3K-Akt pathways were involved in VEGF expression. Four hub genes (COL6A1, SNRPG, COL3A1, and AHI1) associated with VEGF were identified. Among them, COL6A1 was regarded as the key gene associated with anti-VEGF therapy. Further, COL6A1 was upregulated in GBM compared to that in normal brain tissues. COL6A1 overexpression was associated with a poor prognosis. Conclusion: COL6A1 was identified as the key gene associated with anti-VEGF therapy and may provide novel insight into GBM targeted therapy.


Assuntos
Colágeno Tipo VI/metabolismo , Glioblastoma/genética , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , China , Colágeno Tipo VI/genética , Bases de Dados Genéticas , Fatores de Crescimento Endotelial/genética , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes , Glioblastoma/metabolismo , Glioma/genética , Humanos , Estimativa de Kaplan-Meier , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Mapas de Interação de Proteínas , Transcriptoma/genética , Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Centrais de snRNP/genética
18.
Stem Cell Res ; 53: 102351, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33895503

RESUMO

DNA methylation is a common method of gene expression regulation, and this form of regulation occurs in the neurodevelopmental disorder Prader-Willi syndrome (PWS). Gene expression regulation via methylation is important for humans, although there is little understanding of the role of methylation in neuronal differentiation. We characterized the cellular differentiation potential of iPS cells derived from a patient with PWS with abnormal methylation (M-iPWS cells). A comparative genomic hybridization (CGH) array revealed that, unlike iPWS cells (deletion genes type), the abnormally methylated M-iPWS cells had no deletion in the15q11.2-q13 chromosome region. In addition, methylation-specific PCR showed that M-iPWS cells had strong methylation in CpG island of the small nuclear ribonucleoprotein polypeptide N (SNRPN) on both alleles. To assess the effect of abnormal methylation on cell differentiation, the M-iPWS and iPWS cells were induced to differentiate into embryoid bodies (EBs). The results suggest that iPWS and M-iPWS cells are defective at differentiation into ectoderm. Neural stem cells (NSCs) and neurons derived from M-iPWS cells had fewer NSCs and mature neurons with low expression of NSCs and neuronal markers. We conclude that expression of the downstream of genes in the PWS region regulated by methylation is involved in neuronal differentiation.


Assuntos
Células-Tronco Pluripotentes Induzidas , Síndrome de Prader-Willi , Diferenciação Celular , Cromossomos Humanos Par 15/genética , Hibridização Genômica Comparativa , Metilação de DNA , Impressão Genômica , Humanos , Síndrome de Prader-Willi/genética , Proteínas Centrais de snRNP/genética
20.
Med Oncol ; 38(5): 57, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33835288

RESUMO

The small nuclear ribonucleoprotein polypeptides B And B' (SNRPB) is a core component of spliceosome and plays a key role in pre-mRNA splicing. Emerging evidence suggests that it involves in the development of several types of cancer. Our previous study has demonstrated SNRPB is highly expressed in non-small-cell lung cancer (NSCLC) and functions as an oncogene. However, whether SNRPB contributes to cisplatin resistance in NSCLC is still unknown. In this study, we found that SNRPB negatively regulates cisplatin resistance in NSCLC cells. Knocking out of SNRPB could significantly decrease cisplatin-induced cell growth inhibition, cell cycle arrest and apoptosis in H1299 cells. However, enforced expression of SNRPB in H460 cells can markedly promote cisplatin-induced cell growth inhibition, cell cycle arrest and apoptosis. Our results also indicate that overexpression of SNRPB enhances the inhibitory effects of cisplatin on H460 cell-mediated xenograft tumors. Our results suggest that SNRPB may be a prediction marker for NSCLC patients in response to cisplatin-based chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cisplatino/uso terapêutico , Neoplasias Pulmonares/metabolismo , Proteínas Centrais de snRNP/biossíntese , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...