Chad L Myers

Chad L Myers
University of Minnesota Twin Cities | UMN · Department of Computer Science and Engineering

About

364
Publications
30,536
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11,391
Citations
Citations since 2017
105 Research Items
6034 Citations
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201720182019202020212022202302004006008001,000
201720182019202020212022202302004006008001,000

Publications

Publications (364)
Article
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SARS-CoV-2 depends on host cell components for infection and replication. Identification of virus-host dependencies offers an effective way to elucidate mechanisms involved in viral infection and replication. If druggable, host factor dependencies may present an attractive strategy for anti-viral therapy. In this study, we performed genome wide CRI...
Preprint
Full-text available
Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin liga...
Article
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A network of transcription factors (TFs) coordinates transcription with cell cycle events in eukaryotes. Most TFs in the network are phosphorylated by cyclin-dependent kinase (CDK), which limits their activities during the cell cycle. Here, we investigate the physiological consequences of disrupting CDK regulation of the paralogous repressors Yhp1...
Article
Ferroptosis is an important mediator of pathophysiological cell death and an emerging target for cancer therapy. Whether ferroptosis sensitivity is governed by a single regulatory mechanism is unclear. Here, based on the integration of 24 published chemical genetic screens combined with targeted follow-up experimentation, we find that the genetic r...
Article
Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other sy...
Preprint
Full-text available
CRISPR screens are used extensively to systematically interrogate the phenotype-to-genotype problem. In contrast to early CRISPR screens, which defined core cell fitness genes, most current efforts now aim to identify context-specific phenotypes that differentiate a cell line, genetic background or condition of interest, such as a drug treatment. W...
Article
Candida albicans is the leading cause of systemic candidiasis. Effective treatment is threatened by a dearth of antifungal options and the emergence of resistance. Thus, there is an urgent need to identify novel therapeutic targets to expand our antifungal armamentarium. A promising approach is the discovery of essential genes, as most antimicrobia...
Article
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Fungal pathogens pose a global threat to human health, with Candida albicans among the leading killers. Systematic analysis of essential genes provides a powerful strategy to discover potential antifungal targets. Here, we build a machine learning model to generate genome-wide gene essentiality predictions for C. albicans and expand the largest fun...
Article
The continued improvement of combinatorial CRISPR screening platforms necessitates the development of new computational pipelines for scoring combinatorial screening data. Unlike for single-guide RNA (sgRNA) pooled screening platforms, combinatorial scoring for multiplexed systems is confounded by guide design parameters such as the number of gRNAs...
Article
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A common strategy for identifying molecules likely to possess a desired biological activity is to search large databases of compounds for high structural similarity to a query molecule that demonstrates this activity, under the assumption that structural similarity is predictive of similar biological activity. However, efforts to systematically ben...
Article
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Influenza is a serious global health threat that shows varying pathogenicity among different virus strains. Understanding similarities and differences among activated functional pathways in the host responses can help elucidate therapeutic targets responsible for pathogenesis. To compare the types and timing of functional modules activated in host...
Preprint
Influenza is a serious global health threat that shows varying pathogenicity among different virus strains. Understanding similarities and differences among activated functional pathways in the host responses can help elucidate therapeutic targets responsible for pathogenesis. To compare the types and timing of functional modules activated in host...
Article
Environmental impacts on gene networks A phenotype can be affected by genes interacting with other genes, the environment, or both other genes and the environment (a differential interaction). To better understand how these interactions function in yeast, Costanzo et al. mapped gene-gene interactions using single- and double-mutant deletions and te...
Article
Full-text available
Wheat stem rust disease caused by Puccinia graminis f. sp. tritici ( Pgt ) is a global threat to wheat production. Fast evolving populations of Pgt limit the efficacy of plant genetic resistance and constrain disease management strategies. Understanding molecular mechanisms that lead to rust infection and disease susceptibility could deliver novel...
Preprint
Full-text available
Wheat stem rust disease caused by Puccinia graminis f. sp. tritici (Pgt) is a global threat to wheat production. Fast evolving populations of Pgt limit the efficacy of plant genetic resistance and constrain disease management strategies. Understanding molecular mechanisms that lead to rust infection and disease susceptibility could deliver novel st...
Article
Systematic complex genetic interaction studies have provided insight into high-order functional redundancies and genetic network wiring of the cell. Here, we describe a method for screening and quantifying trigenic interactions from ordered arrays of yeast strains grown on agar plates as individual colonies. The protocol instructs users on the trig...
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Essential genes tend to be highly conserved across eukaryotes, but, in some cases, their critical roles can be bypassed through genetic rewiring. From a systematic analysis of 728 different essential yeast genes, we discovered that 124 (17%) were dispensable essential genes. Through whole-genome sequencing and detailed genetic analysis, we investig...
Preprint
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We present FLEX (Functional evaluation of experimental perturbations), a pipeline that leverages several functional annotation resources to establish reference standards for benchmarking human genome-wide CRISPR screen data and methods for analyzing them. We apply FLEX to analyze data from the diverse cell line screens generated by the DepMap proje...
Article
The fate of genes after duplication Gene duplication within an organism is a relatively common event during evolution. However, we cannot predict the fate of the duplicated genes: Will they be lost, evolve, or overlap in function within an organismal lineage or species? Kuzmin et al. explored the fate of duplicated gene function within the yeast Sa...
Article
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The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases, including cancer. Because cancer cells are intrinsically buffered to combat metabolic stress, it is important to understand how cells may adapt to the loss of de novo fatty acid biosynthesis. Here, we use pooled genome-wide CRISPR screens to systematicall...
Article
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Genome‐wide association studies (GWAS) have proven to be a valuable approach for identifying genetic intervals associated with phenotypic variation in Medicago truncatula. These intervals can vary in size, depending on the historical local recombination. Typically, significant intervals span numerous gene models, limiting the ability to resolve hig...
Article
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The evolutionarily conserved centromeric histone H3 variant (Cse4 in budding yeast, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of CENP-A to non-centromeric chromatin contributes to chromosomal instability (CIN) in yeast, fly, and human cells and CENP-A is highly expressed and mislocalized in cancers. Definin...
Article
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Full-text available
Restricting the localization of the histone H3 variant CENP-A (Cse4 in yeast, CID in flies) to centromeres is essential for faithful chromosome segregation. Mislocalization of CENP-A leads to chromosomal instability (CIN) in yeast, fly and human cells. Overexpression and mislocalization of CENP-A has been observed in many cancers and this correlate...
Preprint
Full-text available
The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases including cancer. While several translational efforts have focused on direct perturbation of de novo fatty acid synthesis, only modest responses have been associated with mono-therapies. Since cancer cells are intrinsically buffered to combat metabolic str...
Article
Full-text available
Genetic interactions have been reported to underlie phenotypes in a variety of systems, but the extent to which they contribute to complex disease in humans remains unclear. In principle, genome-wide association studies (GWAS) provide a platform for detecting genetic interactions, but existing methods for identifying them from GWAS data tend to foc...
Article
Chemical genomics has been applied extensively to evaluate small molecules that modulate biological processes in Saccharomyces cerevisiae. Here, we use yeast as a surrogate system for studying compounds that are active against metazoan targets. Large-scale chemical-genetic profiling of thousands of synthetic and natural compounds from the Chinese N...
Article
The construction of genome-wide mutant collections has enabled high-throughput, high-dimensional quantitative characterization of gene and chemical function, particularly via genetic and chemical–genetic interaction experiments. As the throughput of such experiments increases with improvements in sequencing technology and sample multiplexing, appro...
Article
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Chemical-genetic interactions-observed when the treatment of mutant cells with chemical compounds reveals unexpected phenotypes-contain rich functional information linking compounds to their cellular modes of action. To systematically identify these interactions, an array of mutants is challenged with a compound and monitored for fitness defects, g...
Preprint
Full-text available
Genome-wide association studies (GWAS) have proven to be a valuable approach for identifying genetic intervals associated with phenotypic variation in Medicago truncatula. These intervals can vary in size, depending on the historical local recombination near each significant interval. Typically, significant intervals span numerous gene models, limi...
Article
Full-text available
Systematic experimental approaches have led to construction of comprehensive genetic and protein-protein interaction networks for the budding yeast, Saccharomyces cerevisiae. Genetic interactions capture functional relationships between genes using phenotypic readouts, while protein-protein interactions identify physical connections between gene pr...
Article
Centromeric localization of the evolutionarily conserved centromere-specific histone H3 variant CENP-A (Cse4 in yeast) is essential for faithful chromosome segregation. Overexpression and mislocalization of CENP-A leads to chromosome segregation defects in yeast, flies, and human cells. Overexpression of CENP-A has been observed in human cancers; h...
Preprint
Full-text available
Chemical-genetic interactions – observed when the treatment of mutant cells with chemical compounds reveals unexpected phenotypes – contain rich functional information linking compounds to their cellular modes of action. To systematically identify these interactions, an array of mutants is challenged with a compound and monitored for fitness defect...
Article
Trigenic interactions in yeast link bioprocesses To dissect the genotype-phenotype landscape of a cell, it is necessary to understand interactions between genes. Building on the digenic protein-protein interaction network, Kuzmin et al. created a trigenic landscape of yeast by using a synthetic genetic array (see the Perspective by Walhout). Triple...
Preprint
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Background Genome wide association studies (GWAS) have identified thousands of loci linked to hundreds of traits in many different species. However, because linkage equilibrium implicates a broad region surrounding each identified locus, the causal genes often remain unknown. This problem is especially pronounced in non-human, non-model species whe...
Article
Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to β cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to...
Article
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Gamma valerolactone (GVL) treatment of lignocellulosic biomass is a promising technology for degradation of biomass for biofuel production; however, GVL is toxic to fermentative microbes. Using a combination of chemical genomics with the yeast (Saccharomyces cerevisiae) deletion collection to identify sensitive and resistant mutants, and chemical p...
Article
Chemical-genomic approaches that map interactions between small molecules and genetic perturbations offer a promising strategy for functional annotation of uncharacterized bioactive compounds. We recently developed a new high-throughput platform for mapping chemical-genetic (CG) interactions in yeast that can be scaled to screen large compound coll...
Article
Full-text available
Advances in genomics and metabolomics have made clear in recent years that microbial biosynthetic capacities on Earth far exceed previous expectations. This is attributable, in part, to the realization that most microbial natural product (NP) producers harbor biosynthetic machineries not readily amenable to classical laboratory fermentation conditi...
Preprint
Background Gamma valerolactone (GVL) is a promising technology for degradation of biomass for biofuel production; however, GVL has adverse toxicity effects on fermentative microbes. Using a combination of chemical genomics and chemical proteomics we sought to understand the mechanism toxicity and resistance to GVL with the goal of engineering a GVL...
Article
Full-text available
Breast cancer is the second largest cause of cancer death among U.S. women and the leading cause of cancer death among women worldwide. Genome-wide association studies (GWAS) have identified several genetic variants associated with susceptibility to breast cancer, but these still explain less than half of the estimated genetic contribution to the d...
Data
BridGE results from SBCGS CHN cohort based on recessive/dominant combined disease model. (A) List of between-pathway interactions discovered in this cohort; (B) List of within-pathway interactions discovered in this cohort; (C) List of pathway hub interactions discovered in this cohort. (XLSX)
Data
BridGE results from SBCGS CHN (imputed) cohort based on recessive/dominant combined disease model. (A) List of pathway hub interactions discovered in this cohort. (XLSX)
Data
BridGE results from CGEMS cohort based on dominant disease model. (A) List of within-pathway interactions discovered in this cohort; (B) List of pathway hub interactions discovered in this cohort. (XLSX)
Data
Consensus summary of BridGE results across 5 different cohorts. (A) List of between-pathway interactions from the consensus analysis; (B) List of within-pathway interactions from the consensus analysis; (C) List of pathway hub interactions from the consensus analysis; (D) Statistical significance results for consensus analysis; (E) Corresponding pa...
Data
BridGE results from MCS LTN cohort based on dominant disease model. (A) List of pathway hub interactions discovered in this cohort. (XLSX)
Data
Between-pathway interactions involved with glutathione conjugation from SBCGS CHN and MCS LTN cohorts. (XLSX)
Data
BridGE results from BPC3 cohort based on recessive/dominant combined disease model. (A) List of between-pathway interactions discovered in this cohort; (B) List of within-pathway interactions discovered in this cohort; (C) List of pathway hub interactions discovered in this cohort; (D) Corresponding pathway names for Fig 3A. (XLSX)
Data
Replication analysis using BPC3 as discovery cohort and CGEMS as confirmation cohort. (A) List of replicated between-pathway interactions (BPMs); (B) Replication statistics. (XLSX)
Data
Detailed information about interaction between steroid hormone biosynthesis (SHB) and acute myeloid leukemia (AML). (XLSX)
Data
BridGE results from MCS JPN cohort based on dominant combined disease model. (A) List of between-pathway interactions discovered in this cohort; (B) List of within-pathway interactions discovered in this cohort; (C) List of pathway hub interactions discovered in this cohort. (XLSX)
Data
Comparison between BridGE pathways with GWAS breast cancer SNPs. List of pathways identified by BridGE across 5 different cohorts with FDR≤0.25 and their link to GWAS genes. (XLSX)
Preprint
Full-text available
Chemical-genomic approaches that map interactions between small molecules and genetic perturbations offer a promising strategy for functional annotation of uncharacterized bioactive compounds. We recently developed a new high-throughput platform for mapping chemical-genetic (CG) interactions in yeast that can be scaled to screen large compound coll...
Article
A comprehensive view of molecular chaperone function in the cell was obtained through a systematic global integrative network approach based on physical (protein-protein) and genetic (gene-gene or epistatic) interaction mapping. This allowed us to decipher interactions involving all core chaperones (67) and cochaperones (15) of Saccharomyces cerevi...