scholarly journals Genome-Wide CRISPR Screening Identifies the Tumor Suppressor Candidate OVCA2 As a Determinant of Tolerance to Acetaldehyde

2019 ◽  
Vol 169 (1) ◽  
pp. 235-245 ◽  
Author(s):  
Amin Sobh ◽  
Alex Loguinov ◽  
Alessia Stornetta ◽  
Silvia Balbo ◽  
Abderrahmane Tagmount ◽  
...  
Keyword(s):  
Dna Repair ◽  
Tumor Suppressor ◽  
K562 Cells ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Genome Wide ◽  
A Genome ◽  
Cellular Sensitivity ◽  
Genes Encoding ◽  
Increased Sensitivity

Abstract Acetaldehyde, a metabolite of ethanol, is a cellular toxicant and a human carcinogen. A genome-wide CRISPR-based loss-of-function screen in erythroleukemic K562 cells revealed candidate genetic contributors affecting acetaldehyde cytotoxicity. Secondary screening exposing cells to a lower acetaldehyde dose simultaneously validated multiple candidate genes whose loss results in increased sensitivity to acetaldehyde. Disruption of genes encoding components of various DNA repair pathways increased cellular sensitivity to acetaldehyde. Unexpectedly, the tumor suppressor gene OVCA2, whose function is unknown, was identified in our screen as a determinant of acetaldehyde tolerance. Disruption of the OVCA2 gene resulted in increased acetaldehyde sensitivity and higher accumulation of the acetaldehyde-derived DNA adduct N2-ethylidene-dG. Together these results are consistent with a role for OVCA2 in adduct removal and/or DNA repair.

scholarly journals A genome-wide microRNA screen identifies regulators of tetraploid cell proliferation

2018 ◽  
Vol 29 (14) ◽  
pp. 1682-1692 ◽  
Author(s):  
Marc A. Vittoria ◽  
Elizabeth M. Shenk ◽  
Kevin P. O’Rourke ◽  
Amanda F. Bolgioni ◽  
Sanghee Lim ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Proliferative Capacity ◽  
Tetraploid Cell ◽  
Genome Doubling ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Studies

Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, nontransformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these antiproliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive gain-of-function genome-wide screen to identify microRNAs (miRNAs) that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g., miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g., miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via down-regulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.

scholarly journals A genome-wide analysis of Escherichia coli responses to fosfomycin using TraDIS-Xpress reveals novel roles for phosphonate degradation and phosphate transport systems

2020 ◽  
Vol 75 (11) ◽  
pp. 3144-3151 ◽  
Author(s):  
A Keith Turner ◽  
Muhammad Yasir ◽  
Sarah Bastkowski ◽  
Andrea Telatin ◽  
Andrew J Page ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Sugar Metabolism ◽  
Phosphate Transport ◽  
Transport Systems ◽  
Loss Of Function ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Genes Encoding ◽  
The Impact

Abstract Background Fosfomycin is an antibiotic that has seen a revival in use due to its unique mechanism of action and efficacy against isolates resistant to many other antibiotics. In Escherichia coli, fosfomycin often selects for loss-of-function mutations within the genes encoding the sugar importers, GlpT and UhpT. There has, however, not been a genome-wide analysis of the basis for fosfomycin susceptibility reported to date. Methods Here we used TraDIS-Xpress, a high-density transposon mutagenesis approach, to assay the role of all genes in E. coli involved in fosfomycin susceptibility. Results The data confirmed known fosfomycin susceptibility mechanisms and identified new ones. The assay was able to identify domains within proteins of importance and revealed essential genes with roles in fosfomycin susceptibility based on expression changes. Novel mechanisms of fosfomycin susceptibility that were identified included those involved in glucose metabolism and phosphonate catabolism (phnC-M), and the phosphate importer, PstSACB. The impact of these genes on fosfomycin susceptibility was validated by measuring the susceptibility of defined inactivation mutants. Conclusions This work reveals a wider set of genes that contribute to fosfomycin susceptibility, including core sugar metabolism genes and two systems involved in phosphate uptake and metabolism previously unrecognized as having a role in fosfomycin susceptibility.

scholarly journals Genome-Wide Methylation Mapping Using Nanopore Sequencing Technology Identifies Novel Tumor Suppressor Genes in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (8) ◽  
pp. 3937
Author(s):  
Colin F. Davenport ◽  
Tobias Scheithauer ◽  
Alessia Dunst ◽  
Frauke Sophie Bahr ◽  
Marie Dorda ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Suppressor Gene ◽  
Nanopore Sequencing ◽  
Sequencing Technology ◽  
Suppressor Genes ◽  
Genome Wide ◽  
A Genome

Downregulation of multiple tumor suppressor genes (TSGs) plays an important role in cancer formation. Recent evidence has accumulated that cancer progression involves genome-wide alteration of epigenetic modifications, which may cause downregulation of the tumor suppressor gene. Using hepatocellular carcinoma (HCC) as a system, we mapped 5-methylcytosine signal at a genome-wide scale using nanopore sequencing technology to identify novel TSGs. Integration of methylation data with gene transcription profile of regenerated liver and primary HCCs allowed us to identify 10 potential tumor suppressor gene candidates. Subsequent validation led us to focus on functionally characterizing one candidate—glucokinase (GCK). We show here that overexpression of GCK inhibits the proliferation of HCC cells via induction of intracellular lactate accumulation and subsequently causes energy crisis due to NAD+ depletion. This suggests GCK functions as a tumor suppressor gene and may be involved in HCC development. In conclusion, these data provide valuable clues for further investigations of the process of tumorigenesis in human cancer.

scholarly journals A genome-wide miRNA screen identifies regulators of tetraploid cell proliferation

2018 ◽  
Author(s):  
Marc A. Vittoria ◽  
Elizabeth M. Shenk ◽  
Kevin P. O’Rourke ◽  
Amanda F. Bolgioni ◽  
Sanghee Lim ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Proliferative Capacity ◽  
Tetraploid Cell ◽  
Genome Doubling ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Studies

AbstractTetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, non-transformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these anti-proliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive, gain-of-function genome-wide screen to identify miRNAs that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g. miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g. miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via downregulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.

scholarly journals A Nonsense Variant in Hephaestin Like 1 (HEPHL1) Is Responsible for Congenital Hypotrichosis in Belted Galloway Cattle

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 643
Author(s):  
Thibaud Kuca ◽  
Brandy M. Marron ◽  
Joana G. P. Jacinto ◽  
Julia M. Paris ◽  
Christian Gerspach ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Homozygosity Mapping ◽  
Mendelian Inheritance ◽  
Large Animal Model ◽  
Large Animal ◽  
Loss Of Function ◽  
Protein Coding ◽  
Positional Candidate ◽  
Genome Wide ◽  
A Genome

Genodermatosis such as hair disorders mostly follow a monogenic mode of inheritance. Congenital hypotrichosis (HY) belong to this group of disorders and is characterized by abnormally reduced hair since birth. The purpose of this study was to characterize the clinical phenotype of a breed-specific non-syndromic form of HY in Belted Galloway cattle and to identify the causative genetic variant for this recessive disorder. An affected calf born in Switzerland presented with multiple small to large areas of alopecia on the limbs and on the dorsal part of the head, neck, and back. A genome-wide association study using Swiss and US Belted Galloway cattle encompassing 12 cases and 61 controls revealed an association signal on chromosome 29. Homozygosity mapping in a subset of cases refined the HY locus to a 1.5 Mb critical interval and subsequent Sanger sequencing of protein-coding exons of positional candidate genes revealed a stop gain variant in the HEPHL1 gene that encodes a multi-copper ferroxidase protein so-called hephaestin like 1 (c.1684A>T; p.Lys562*). A perfect concordance between the homozygous presence of this most likely pathogenic loss-of-function variant and the HY phenotype was found. Genotyping of more than 700 purebred Swiss and US Belted Galloway cattle showed the global spread of the mutation. This study provides a molecular test that will permit the avoidance of risk matings by systematic genotyping of relevant breeding animals. This rare recessive HEPHL1-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002230-9913).

scholarly journals MEN4 and CDKN1B mutations: the latest of the MEN syndromes

2017 ◽  
Vol 24 (10) ◽  
pp. T195-T208 ◽  
Author(s):  
Rami Alrezk ◽  
Fady Hannah-Shmouni ◽  
Constantine A Stratakis
Keyword(s):  
Tumor Suppressor ◽  
Neuroendocrine Tumors ◽  
Pituitary Adenomas ◽  
Wide Spectrum ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Putative Tumor Suppressor

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor geneMEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not haveMEN1mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressorCDKN1B. The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations inCDKN1Bwere also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role forCDKN1Bas a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

Abstract 5340: Cardiac Resynchronization Therapy Corrects Dyssynchrony-induced Regional Gene Expression Changes on a Genomic Level

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Andreas S Barth ◽  
Takeshi Aiba ◽  
Victoria Halperin ◽  
Deborah DiSilvestre ◽  
Chakir Khalid ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Resynchronization Therapy ◽  
Cardiac Resynchronization ◽  
Functional Improvement ◽  
Large Animal ◽  
Atrial Pacing ◽  
Resynchronization Therapy ◽  
Genome Wide ◽  
A Genome ◽  
Genes Encoding

Purpose: Cardiac Resynchronization Therapy (CRT) improves symptoms and reduces mortality in patients with heart failure (HF). To characterize the molecular processes associated with functional improvement in CRT, we used a genomic approach in a large animal HF model. Methods: After creation of a left bundle branch block (LBBB), dogs in the HF group were subjected to either rapid atrial pacing with 200 bpm for 6 weeks (dyssynchronous HF, DHF, n=10), or 3 weeks of atrial pacing followed by 3 weeks of biventricular stimulation at 200bpm (CRT, n=9). Control animals without LBBB were not paced (NF, n=11). After 6 weeks, RNA from anterior and lateral regions of the LV was hybridized onto canine 44K arrays. Statistical Analysis of Microarrays (SAM) was used for data analysis. Results: Echocardiographically, CRT led to a significant increase in stroke volume (+27%, p=0.03) which translated into a non-significant increase in EF (DHF 25±4%; CRT 31±3% (p=0.15); NF 67±3%). A multiclass analysis of NF, DHF and CRT animals identified 1050 differentially expressed transcripts between anterior and lateral walls with a false discovery rate of 5%. For all these transcripts, dyssynchrony-induced expression changes were reversed by CRT to levels of NF hearts. As a result, CRT samples clustered with NF rather than DHF samples. Of particular interest were genes encoding for signal transduction pathways and contractile processes. Conclusions: By using a whole genome approach, we demonstrate a profound effect of electrical activation on the regional cardiac transcriptome. This is the first study showing that dyssynchrony-induced gene expression changes can be corrected by CRT on a genome-wide level.

scholarly journals Genome-wide survey of sucrose non-fermenting 1-related protein kinase 2 in Rosaceae and expression analysis of PbrSnRK2 in response to ABA stress

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Guodong Chen ◽  
Jizhong Wang ◽  
Xin Qiao ◽  
Cong Jin ◽  
Weike Duan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Gene Family ◽  
Structural Characteristics ◽  
Purifying Selection ◽  
Related Protein ◽  
Rosaceae Species ◽  
Genome Wide ◽  
A Genome ◽  
Genes Encoding ◽  
Genome Wide Survey

Abstract Background The members of the sucrose non-fermenting 1-related protein kinase 2 (SnRK2) family are specific serine/threonine protein kinases in plants that play important roles in stress signal transduction and adaptation. Because of their positive regulatory roles in response to adverse conditions, the genes encoding thes proteins are considered potential candidates for breeding of plants for disease resistance and genetic improvement. However, there is far less information about this kinase family, and the function of these genes has not been explored in Rosaceae. Results A genome-wide survey and analysis of the genes encoding members of the SnRK2 family were performed in pear (Pyrus bretschneideri) and seven other Rosaceae species. A total of 71 SnRK2 genes were identified from the eight Rosaceae species and classified into three subgroups based on phylogenetic analysis and structural characteristics. Purifying selection played a crucial role in the evolution of SnRK2 genes, and whole-genome duplication and dispersed duplication were the primary forces underlying the characteristics of the SnRK2 gene family in Rosaceae. Transcriptome data and qRT-PCR assay results revealed that the distribution of PbrSnRK2s was very extensive, including across the roots, leaves, pollen, styles, and flowers, although most of them were mainly expressed in leaves. In addition, under stress conditions, the transcript levels of some of the genes were upregulated in leaves in response to ABA treatment. Conclusions This study provides useful information and a theoretical introduction for the study of the evolution, expression, and functions of the SnRK2 gene family in plants.

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