Yuval Tabach - Academia.edu (original) (raw)

Papers by Yuval Tabach

NAR Genomics and Bioinformatics

Conservation is a strong predictor for the pathogenicity of single-nucleotide variants (SNVs). Ho... more Conservation is a strong predictor for the pathogenicity of single-nucleotide variants (SNVs). However, some positions that present complex conservation patterns across vertebrates stray from this paradigm. Here, we analyzed the association between complex conservation patterns and the pathogenicity of SNVs in the 115 disease-genes that had sufficient variant data. We show that conservation is not a one-rule-fits-all solution since its accuracy highly depends on the analyzed set of species and genes. For example, pairwise comparisons between the human and 99 vertebrate species showed that species differ in their ability to predict the clinical outcomes of variants among different genes using conservation. Furthermore, certain genes were less amenable for conservation-based variant prediction, while others demonstrated species that optimize prediction. These insights led to developing EvoDiagnostics, which uses the conservation against each species as a feature within a random-forest...

Science Advances

Cancer is a predominant disease across animals. We applied a comparative genomics approach to sys... more Cancer is a predominant disease across animals. We applied a comparative genomics approach to systematically characterize genes whose conservation levels correlate positively (PC) or negatively (NC) with cancer resistance estimates across 193 vertebrates. Pathway analysis reveals that NC genes are enriched for metabolic functions and PC genes in cell cycle regulation, DNA repair, and immune response, pointing to their corresponding roles in mediating cancer risk. We find that PC genes are less tolerant to loss-of-function (LoF) mutations, are enriched in cancer driver genes, and are associated with germline mutations that increase human cancer risk. Their relevance to cancer risk is further supported via the analysis of mouse functional genomics and cancer mortality of zoo mammals’ data. In sum, our study describes a cross-species genomic analysis pointing to candidate genes that may mediate human cancer risk.

Toxins, Dec 20, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

iScience, 2020

PhenolaTi is an advanced non-toxic anticancer chemotherapy; this inert bis(phenolato)bis(alkoxo) ... more PhenolaTi is an advanced non-toxic anticancer chemotherapy; this inert bis(phenolato)bis(alkoxo) Ti(IV) complex demonstrates the intriguing combination of high and wide efficacy with no detected toxicity in animals. Here we unravel the cellular pathways involved in its mechanism of action by a first genome study on Ti(IV)-treated cells, using an attuned RNA sequencing-based available technology. First, phenolaTi induced apoptosis and cell-cycle arrest at the G2/M phase in MCF7 cells. Second, the transcriptome of the treated cells was analyzed, identifying alterations in pathways relating to protein translation, DNA damage, and mitochondrial eruption. Unlike for common metallodrugs, electrophoresis assay showed no inhibition of DNA polymerase activity. Reduced in vitro cytotoxicity with added endoplasmic reticulum (ER) stress inhibitor supported the ER as a putative cellular target. Altogether, this paper reveals a distinct ER-related mechanism by the Ti(IV) anticancer coordination complex, paving the way for wider applicability of related techniques in mechanistic analyses of metallodrugs.

Nucleic Acids Research, 2016

MicroRNAs (miRNAs) impinge on the translation and stability of their target mRNAs, and play key r... more MicroRNAs (miRNAs) impinge on the translation and stability of their target mRNAs, and play key roles in development, homeostasis and disease. The gene regulation mechanisms they instigate are largely mediated through the CCR4-NOT deadenylase complex, but the molecular events that occur on target mRNAs are poorly resolved. We observed a broad convergence of interactions of germ granule and P body mRNP components on AIN-1/GW182 and NTL-1/CNOT1 in Caenorhabditis elegans embryos. We show that the miRISC progressively matures on the target mRNA from a scanning form into an effector mRNP particle by sequentially recruiting the CCR4-NOT complex, decapping and decay, or germ granule proteins. Finally, we implicate intrinsically disordered proteins, key components in mRNP architectures, in the embryonic function of lsy-6 miRNA. Our findings define dynamic steps of effector mRNP assembly in miRNA-mediated silencing, and identify a functional continuum between germ granules and P bodies in the C. elegans embryo.

Nature Communications, Nov 9, 2021

Over the next decade, more than a million eukaryotic species are expected to be fully sequenced. ... more Over the next decade, more than a million eukaryotic species are expected to be fully sequenced. This has the potential to improve our understanding of genotype and phenotype crosstalk, gene function and interactions, and answer evolutionary questions. Here, we develop a machine-learning approach for utilizing phylogenetic profiles across 1154 eukaryotic species. This method integrates co-evolution across eukaryotic clades to predict functional interactions between human genes and the context for these interactions. We benchmark our approach showing a 14% performance increase (auROC) compared to previous methods. Using this approach, we predict functional annotations for less studied genes. We focus on DNA repair and verify that 9 of the top 50 predicted genes have been identified elsewhere, with others previously prioritized by high-throughput screens. Overall, our approach enables better annotation of function and functional interactions and facilitates the understanding of evolutionary processes underlying co-evolution. The manuscript is accompanied by a webserver available at: https://mlpp.cs.huji.ac.il.

Accompanying files to the publication "CladeOScope: elucidating functional interactions via ... more Accompanying files to the publication "CladeOScope: elucidating functional interactions via a clade co-evolution prism" The files attached here constitute the phylogenetic profiling matrices required to reproduce the method and its comparisons as detailed in the publication. For more details and the code required to reproduce the publication please read the publication and visit the following github repository: https://github.com/dst1/CladeOScope To cite our paper use the following citation (bibtex): <pre><code>{bibtex - TBD}</code></pre>

www.molecularsystemsbiology.com

Toxins, 2021

Pathologic expansions of DNA nucleotide tandem repeats may generate toxic RNA that triggers disea... more Pathologic expansions of DNA nucleotide tandem repeats may generate toxic RNA that triggers disease phenotypes. RNA toxicity is the hallmark of multiple expansion repeat disorders, including myotonic dystrophy type 1 (DM1). To date, there are no available disease-modifying therapies for DM1. Our aim was to use drug repositioning to ameliorate the phenotype of affected individuals in a nematode model of DM1. As the RNA interference pathway plays a key role in mediating RNA toxicity, we investigated the effect of aurintricarboxylic acid. We demonstrated that by perturbing the RNA interference machinery using aurintricarboxylic acid, we could annihilate the RNA toxicity and ameliorate the phenotype. As our approach targets a universal disease mechanism, it is potentially relevant for more expansion repeat disorders.

npj Breast Cancer, 2021

It was hypothesized that variants in underexplored homologous recombination repair (HR) genes cou... more It was hypothesized that variants in underexplored homologous recombination repair (HR) genes could explain unsolved multiple-case breast cancer (BC) families. We investigated HR deficiency (HRD)-associated mutational signatures and second hits in tumor DNA from familial BC cases. No candidates genes were associated with HRD in 38 probands previously tested negative with gene panels. We conclude it is unlikely that unknown HRD-associated genes explain a large fraction of unsolved familial BC.

bioRxiv, 2021

Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases. These repeats ... more Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases. These repeats cause RNA toxicity and trigger multisystemic symptoms that worsen with age. RNA toxicity can trigger, through an unclear mechanism, severe disease manifestation in infants that inherited repeats from their mothers. Here we show in Caenorhabditis elegans how RNA interference machinery causes intergenerational toxicity through inheritance of siRNAs derived from CUG repeats. The maternal repeat-derived small RNAs cause transcriptomic changes in the offspring, reduce motility and shorten lifespan. However, the toxicity phenotypes in the offspring can be rescued by perturbing the RNAi machinery in affected mothers. This points to a novel mechanism linking maternal bias and the RNAi machinery and suggests that toxic RNA is transmitted to offspring and causes disease phenotypes through intergenerational epigenetic inheritance.

Nature Communications, 2021

ABSTRACTCancer is an evolutionarily conserved disease that occurs in a wide variety of species. W... more ABSTRACTCancer is an evolutionarily conserved disease that occurs in a wide variety of species. We applied a comparative genomics approach to systematically characterize the genes whose conservation levels significantly correlates positively (PC) or negatively (NC) with a broad spectrum of cancer-resistance estimates, computed across almost 200 vertebrate species. PC genes are enriched in pathways relevant to tumor suppression including cell cycle, DNA repair, and immune response, while NC genes are enriched with a host of metabolic pathways. The conservation levels of the PC and NC genes in a species serve to build the first genomics-based predictor of its cancer resistance score. We find that PC genes are less tolerant to loss of function (LoF) mutations, are enriched in cancer driver genes and are associated with germline mutations that increase human cancer risk. Furthermore, their expression levels are associated with lifetime cancer risk across human tissues. Finally, their kn...

eLife, 2021

Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Ret... more Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here, we used an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA-approved drugs led to three promising targets, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). The drugs targeting these three proteins (Pacritinib, DMF, and EPO) were able to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appeared to converge on Nuclear Factor Kappa B (NF-κB) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.

Molecular Metabolism, 2020

Objective: The endocannabinoid (eCB) system is increasingly recognized as being crucially importa... more Objective: The endocannabinoid (eCB) system is increasingly recognized as being crucially important in obesity-related hepatic steatosis. By activating the hepatic cannabinoid-1 receptor (CB 1 R), eCBs modulate lipogenesis and fatty acid oxidation. However, the underlying molecular mechanisms are largely unknown. Methods: We combined unbiased bioinformatics techniques, mouse genetic manipulations, multiple pharmacological, molecular, and cellular biology approaches, and genomic sequencing to systematically decipher the role of the hepatic CB 1 R in modulating fat utilization in the liver and explored the downstream molecular mechanisms. Results: Using an unbiased normalized phylogenetic profiling analysis, we found that the CB 1 R evolutionarily coevolves with peroxisome proliferator-activated receptor-alpha (PPARa), a key regulator of hepatic lipid metabolism. In diet-induced obese (DIO) mice, peripheral CB 1 R blockade (using AM6545) induced the reversal of hepatic steatosis and improved liver injury in WT, but not in PPARa À/À mice. The antisteatotic effect mediated by AM6545 in WT DIO mice was accompanied by increased hepatic expression and activity of PPARa as well as elevated hepatic levels of the PPARa-activating eCB-like molecules oleoylethanolamide and palmitoylethanolamide. Moreover, AM6545 was unable to rescue hepatic steatosis in DIO mice lacking liver sirtuin 1 (SIRT1), an upstream regulator of PPARa. Both of these signaling molecules were modulated by the CB 1 R as measured in hepatocytes exposed to lipotoxic conditions or treated with CB 1 R agonists in the absence/presence of AM6545. Furthermore, using microRNA transcriptomic profiling, we found that the CB 1 R regulated the hepatic expression, acetylation, and transcriptional activity of p53, resulting in the enhanced expression of miR-22, which was found to specifically target SIRT1 and PPARa. Conclusions: We provide strong evidence for a functional role of the p53/miR-22/SIRT1/PPARa signaling pathway in potentially mediating the antisteatotic effect of peripherally restricted CB 1 R blockade.

SSRN Electronic Journal, 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spillover infection in December ... more The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spillover infection in December 2019 has caused an unprecedented pandemic. SARS-CoV-2, as other coronaviruses, binds its target cells through the angiotensin-converting enzyme 2 (ACE2) receptor. Accordingly, this makes ACE2 research essential for understanding the zoonotic nature of coronaviruses and identifying novel drugs. Here we present a systematic analysis of the ACE2 conservation and coevolution protein network across 1,671 eukaryotes, revealing an unexpected conservation pattern in specific metazoans, plants, fungi, and protists. We identified the co-evolved protein network and pinpointed a list of drugs that target this network by using data integration from different sources. Our computational analysis found widely used drugs such as nonsteroidal anti-inflammatory drugs and vasodilators. These drugs are expected to perturb the ACE2 network affecting infectivity as well as the pathophysiology of the disease.