scholarly journals Cross-talks of glycosylphosphatidylinositol biosynthesis with glycosphingolipid biosynthesis and ER-associated degradation

2019 ◽  
Author(s):  
Yicheng Wang ◽  
Yusuke Maeda ◽  
Yishi Liu ◽  
Yoko Takada ◽  
Akinori Ninomiya ◽  
...  
Keyword(s):  
Quality Control ◽  
Plasma Membranes ◽  
Genetic Screen ◽  
Side Chain ◽  
Gm1 Ganglioside ◽  
Er Quality Control ◽  
Functional Relationships ◽  
Genome Wide ◽  
A Genome ◽  
Glycosphingolipid Biosynthesis

Glycosylphosphatidylinositol (GPI)-anchored proteins and glycosphingolipids interact with each other in the mammalian plasma membranes, forming dynamic microdomains. How their interaction starts in the cells has been unclear. Here, based on a genome-wide CRISPR-Cas9 genetic screen for genes required for GPI side-chain modification by galactose in the Golgi apparatus, we report that β1,3-galactosyltransferase 4 (B3GALT4), also called GM1 ganglioside synthase, additionally functions in transferring galactose to the N-acetylgalactosamine side-chain of GPI. Furthermore, B3GALT4 requires lactosylceramide for the efficient GPI side-chain galactosylation. Thus, our work demonstrates previously unexpected evolutionary and functional relationships between GPI-anchored proteins and glycosphingolipids in the Golgi. Through the same screening, we also show that GPI biosynthesis in the endoplasmic reticulum (ER) is severely suppressed by ER-associated degradation to prevent GPI accumulation when the transfer of synthesized GPI to proteins is defective. Our data demonstrates cross-talks of GPI biosynthesis with glycosphingolipid biosynthesis and the ER quality control system.

Genomic determinants of prognosis in esophageal adenocarcinoma: Using computational methods to account for gene-gene interactions.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 42-42
Author(s):  
Eric Morgen ◽  
Xiaowei Shen ◽  
Thomas L. Vaughan ◽  
David Whiteman ◽  
Anna H. Wu ◽  
...  
Keyword(s):  
Quality Control ◽  
Esophageal Adenocarcinoma ◽  
Population Stratification ◽  
Cox Proportional Hazards ◽  
Interactive Effects ◽  
Gene Interactions ◽  
P Value ◽  
Tumor Resistance ◽  
Genome Wide ◽  
A Genome

42 Background: Methods of stratifying esophageal adenocarcinoma patients into prognostic groups are needed, as are new insights into genetic determinants of disease behaviour. Prognosis is likely to have non-negligible genetic influences, as mediated by host responses to tumor, resistance to therapeutic side-effects, and/or an influence on tumor development. Prior studies have used candidate-gene approaches. We took an alternative approach, using an unbiased, genome-wide approach, and novel analytic methods that may be better able to detect multi-gene interactions, which may contribute the majority of genetic effects for many clinical phenotypes. Methods: Germline DNA from a Toronto-based cohort of EAC patients (n=270) was analyzed by Omni1 Quad microarray as part of the BEAGESS initiative. Quality control and analysis was performed using PLINK, R, and GenABEL software packages. A Cox proportional hazards (CPH) model for progression-free survival tested each polymorphism for independent effects at a genome-wide significance level of P < 1E-07, adjusting for population stratification. While classical analysis has limited ability to detect gene-gene interactions, a Random Survival Forest algorithm was used to detect effects based on the complex interactions among top 1,000 polymorphisms by p-value ranking. Results: After data cleaning and standard GWAS quality control procedures, there were 735,309 SNPs and 245 patients remaining for analysis. The CPH model, adjusted for population stratification, produced a satisfactory Q-Q plot, and showed one SNP (rs7844673, Chr 8) that was significant at p=7.8E-8. In addition, Random Forest based variable selection produced a set of 20 polymorphisms that (1) reproduced 86% of the predictive ability of the full 1000 variables, and (2) also included the #3 ranked polymorphism by CPH modeling (rs9290822, Chr 3) upstream of the IGF2BP2 gene. Conclusions: A genome-wide approach has discovered two previously undescribed SNPs with a potential influence on EAC prognosis via a combination of independent and interactive effects. Validation in an independent cohort is currently being pursued.

scholarly journals Spatial sequestration and detoxification of Huntingtin by the ribosome quality control complex

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Junsheng Yang ◽  
Xinxin Hao ◽  
Xiuling Cao ◽  
Beidong Liu ◽  
Thomas Nyström
Keyword(s):  
Quality Control ◽  
Regulatory System ◽  
Super Resolution ◽  
Age Related ◽  
Genome Wide ◽  
A Genome ◽  
Polyglutamine Expansions ◽  
Key Factor ◽  
Super Resolution Microscopy ◽  
Control Complex

Huntington disease (HD) is a neurological disorder caused by polyglutamine expansions in mutated Huntingtin (mHtt) proteins, rendering them prone to form inclusion bodies (IB). We report that in yeast, such IB formation is a factor-dependent process subjected to age-related decline. A genome-wide, high-content imaging approach, identified the E3 ubiquitin ligase, Ltn1 of the ribosome quality control complex (RQC) as a key factor required for IB formation, ubiquitination, and detoxification of model mHtt. The failure of ltn1∆ cells to manage mHtt was traced to another RQC component, Tae2, and inappropriate control of heat shock transcription factor, Hsf1, activity. Moreover, super-resolution microscopy revealed that mHtt toxicity in RQC-deficient cells was accompanied by multiple mHtt aggregates altering actin cytoskeletal structures and retarding endocytosis. The data demonstrates that spatial sequestration of mHtt into IBs is policed by the RQC-Hsf1 regulatory system and that such compartmentalization, rather than ubiquitination, is key to mHtt detoxification.

scholarly journals Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Kifayathullah Liakath-Ali ◽  
Valerie E. Vancollie ◽  
Emma Heath ◽  
Damian P. Smedley ◽  
Jeanne Estabel ◽  
...  
Keyword(s):  
Genetic Screen ◽  
Reverse Genetic ◽  
Genome Wide ◽  
A Genome ◽  
Reverse Genetic Screen

scholarly journals A genome-wide association study identifies novel susceptibility loci in chronic Chagas cardiomyopathy

2021 ◽  
Author(s):  
Desiré Casares-Marfil ◽  
Mariana Strauss ◽  
Pau Bosch-Nicolau ◽  
María Silvina Lo Presti ◽  
Israel Molina ◽  
...  
Keyword(s):  
Association Study ◽  
Chagas Disease ◽  
Latin American ◽  
In Silico ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Chagas Cardiomyopathy ◽  
Functional Relationships ◽  
Genome Wide ◽  
A Genome

Abstract Background Chagas disease is an infectious disease caused by the parasite Trypanosoma cruzi and is endemic from Latin American countries. The goal of our study was to identify novel genetic loci associated with chronic Chagas cardiomyopathy development in Chagas disease patients from different Latin American populations. Methods We performed a cross-sectional, nested case-control study including three sample collections from Colombia, Argentina and Bolivia. Samples were genotyped to conduct a genome-wide association study (GWAS). These results were meta-analyzed with summary statistic data from Brazil, gathering a total of 3,413 Chagas disease patients. To identify the functional impact of the associated variant and its proxies we performed an in silico analysis of this region. Results The meta-analysis revealed a novel genome-wide statistically significant association with chronic Chagas cardiomyopathy development in rs2458298 (OR=0.90, 95%CI=0.87-0.94, p-value=3.27x10 -08), nearby the SAC3D1 gene. In addition, further in silico analyses displayed functional relationships between the associated variant and the SNX15, BAFT2 and FERMT3 genes, related to cardiovascular traits. Conclusions Our findings support the role of the host genetic factors in the susceptibility to the development of the chronic cardiac form of this neglected disease.

scholarly journals CAM: a quality control pipeline for MNase-seq data

2017 ◽  
Author(s):  
Sheng’en Hu ◽  
Xiaolan Chen ◽  
Ji Liao ◽  
Yiqing Chen ◽  
Chengchen Zhao ◽  
...  
Keyword(s):  
Quality Control ◽  
High Throughput Sequencing ◽  
Micrococcal Nuclease ◽  
Functional Regions ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
Micrococcal Nuclease Digestion ◽  
A Genome ◽  
Nuclease Digestion ◽  
Wide Scale

AbstractNucleosome organization affects the accessibility of cis-elements to trans-acting factors. Micrococcal nuclease digestion followed by high-throughput sequencing (MNase-seq) is the most popular technology used to profile nucleosome organization on a genome-wide scale. Evaluating the data quality of MNase-seq data remains challenging, especially in mammalian. There is a strong need for a convenient and comprehensive approach to obtain dedicated quality control (QC) for MNase-seq data analysis. Here we developed CAM, which is a comprehensive QC pipeline for MNase-seq data. The CAM pipeline provides multiple informative QC measurements and nucleosome organization profiles on different potentially functional regions for given MNase-seq data. CAM also includes 268 historical MNase-seq datasets from human and mouse as a reference atlas for unbiased assessment. CAM is freely available at: http://www.tongji.edu.cn/~zhanglab/CAM

scholarly journals Use of a genome-wide haploid genetic screen to identify treatment predicting factors: a proof-of-principle study in pancreatic cancer

Oncotarget ◽  
2017 ◽  
Vol 8 (38) ◽  
pp. 63635-63645 ◽  
Author(s):  
Yuk Ting Ma ◽  
Sarah M. Leonard ◽  
Naheema Gordon ◽  
Jennifer Anderton ◽  
Claire James ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Genetic Screen ◽  
Predicting Factors ◽  
Genome Wide ◽  
A Genome ◽  
Proof Of Principle

scholarly journals Results of a genome-wide genetic screen for panic disorder

1998 ◽  
Vol 81 (2) ◽  
pp. 139-147 ◽  
Author(s):  
J.A. Knowles ◽  
A.J. Fyer ◽  
V.J. Vieland ◽  
M.M. Weissman ◽  
S.E. Hodge ◽  
...  
Keyword(s):  
Panic Disorder ◽  
Genetic Screen ◽  
Genome Wide ◽  
A Genome

Panic disorder is unlikely to be a homogeneous autosomal dominant disorder: Results of a genome-wide genetic screen

1996 ◽  
Vol 39 (7) ◽  
pp. 567
Author(s):  
J.A. Knowles ◽  
V.J. Vieland ◽  
M.M. Weissman ◽  
G. Heiman ◽  
G. de Jesus ◽  
...  
Keyword(s):  
Panic Disorder ◽  
Autosomal Dominant ◽  
Genetic Screen ◽  
Autosomal Dominant Disorder ◽  
Genome Wide ◽  
A Genome

scholarly journals Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion

2021 ◽  
Author(s):  
Simon Haeussler ◽  
Assa Yeroslaviz ◽  
Stéphane G Rolland ◽  
Sebastian Luehr ◽  
Eric J Lambie ◽  
...  
Keyword(s):  
Quality Control ◽  
Caenorhabditis Elegans ◽  
Environmental Changes ◽  
Mitochondrial Dynamics ◽  
Rnai Screen ◽  
Mitochondrial Fusion ◽  
Mitochondrial Homeostasis ◽  
Genome Wide ◽  
A Genome ◽  
Quality Control Mechanism

Abstract Mitochondrial dynamics plays an important role in mitochondrial quality control and the adaptation of metabolic activity in response to environmental changes. The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin, and identified 299 suppressors and 86 enhancers. Approximately 90% of these 385 genes are conserved in humans, and one third of the conserved genes have been implicated in human disease. Furthermore, many have roles in developmental processes, which suggests that mitochondrial function and the response to stress are defined during development and maintained throughout life. Our dataset primarily contains mitochondrial enhancers and non-mitochondrial suppressors of UPRmt, indicating that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function, which, when disrupted, can be compensated for by many different cellular processes. Analysis of the subsets ‘non-mitochondrial enhancers’ and ‘mitochondrial suppressors’ suggests that organellar contact sites, especially between the ER and mitochondria, are of importance for mitochondrial homeostasis. In addition, we identified several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants and found a potential link between pre-mRNA splicing and UPRmt activation.

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