Biology subjects

Petsalaki, E.

Publications and source records attributed to Petsalaki, E..

23 records · Page 2Linked to original sources

bioRxiv2020

CEN-tools: An integrative platform to identify the contexts of essential genes

I.An emerging theme from large-scale genetic screens that identify genes essential for fitness of a cell, is that essentiality of a given gene is highly context-specific and depends on a number of genetic and environmental factors. Identification of such contexts could be the key to defining the function of the gene and also to develop novel therapeutic interventions. Here we present CEN-tools (Context-specific Essentiality Network-tools), a website and an accompanying python package, in which users can interrogate the essentiality of a gene from large-scale genome-scale CRISPR screens in a number of biological contexts including tissue of origin, mutation profiles, expression levels, and drug response levels. We show that CEN-tools is suitable for both the systematic identification of genetic dependencies as well as for targeted queries into the dependencies of specific user-selected genes. The associations between genes and a given context within CEN-tools are represented as dependency networks (CENs) and we demonstrate the utility of these networks in elucidating novel gene functions. In addition, we integrate the dependency networks with existing protein-protein interaction networks to reveal context-dependent essential cellular pathways in cancer cells. Together, we demonstrate the applicability of CEN-tools in aiding the current efforts to define the human cellular dependency map.

systems biology↗

bioRxiv2020

Chromosomal arrangement of synthetic lethal gene pairs: repulsion or attraction?

Synthetic lethal interactions are of paramount importance both in biology and in medicine, and hence increasing efforts have been devoted to their systematic identification. Our previous computational analysis revealed that in prokaryotic species, synthetic lethal genes tend to be further away in chromosomes than random (i.e. repulsion), which was shown to provide bacterial genomes with greater robustness to large-scale DNA deletions. To test the generalizability of this observation in eukaryotic genomes, we leveraged the wealth of experimentally determined synthetic lethal genetic interactions of yeast that are curated in the BioGRID (Biological General Repository for Interaction Datasets) database. We observed an opposite trend that is the genomic proximity of synthetic lethal gene pairs both on the 2D and 3D chromosomal space of the yeast genome (i.e. 2D and 3D attraction). To gain mechanistic insights into the origin of the attraction of synthetic lethal gene pairs in S. cerevisiae, we characterized four classes of genes, in which synthetic lethal interactions are enriched and partly explain the observed patterns of genomic attraction: i) gene pairs operating on the same pathways, 2) co-expressed genes, 3) gene pairs whose protein products physically interact and 4) the paralogs. However, our analysis revealed that the contribution of these four types of genes is not sufficient to fully explain the observed 2D and 3D attraction of synthetic lethal gene pairs and hence its evolutionary origin still remains as an open question. Significance statementUnravelling the organizing principles underlying gene arrangements is one of the fundamental questions of research in evolutionary biology. One understudied aspect of this organization is the relative chromosomal arrangement of synthetic lethal gene pairs. In this study, by analyzing a wealth of synthetic lethality data in yeast, we provide evidence that synthetic lethal gene pairs tend to be attracted to each other both on 2D and 3D chromosomal space of the yeast genome. This observation is in sharp contrast with the repulsion of synthetic lethal (metabolic) gene pairs that we observed previously in bacterial genomes. Characterizing the evolutionary forces underlying this genomic pattern in yeast can open the door towards an evolutionary theory of genome organization in eukaryotes.

evolutionary biology↗

bioRxiv2019

Proteome-wide inference of protein kinase regulatory circuits

Complex networks of regulatory relationships between protein kinases comprise a major component of intracellular signaling. Although many kinase-kinase regulatory relationships have been described in detail, these are biased towards well-studied kinases while the majority of possible relationships remains unexplored. Here, we implement data-driven, unbiased methods to predict human kinase-kinase regulatory relationships and whether they have activating or inhibiting effects. We incorporate high-throughput data, kinase specificity profiles, and structural information to produce our predictions. The results successfully recapitulate previously annotated regulatory relationships and can reconstruct known signaling pathways from the ground up. The full network of predictions is relatively sparse, with the vast majority of relationships assigned low probabilities. However, it nevertheless suggests denser modes of inter-kinase regulation than normally considered in intracellular signaling research.

systems biology↗

bioRxiv2018

Systematic Characterization of RhoGEF/RhoGAP Regulatory Proteins Reveals Organization Principles of Rho GTPase Signaling

Rho GTPases control cell morphogenesis and thus fundamental processes in all eukaryotes. They are regulated by 145 RhoGEF and RhoGAP multi-domain proteins in humans. How the Rho signaling system is organized to generate localized responses in cells and prevent their spreading is not understood. Here, we systematically characterized the substrate specificities, localization and interactome of the RhoGEFs/RhoGAPs and revealed their critical role in contextualizing and spatially delimiting Rho signaling. They localize to multiple compartments providing positional information, are extensively interconnected to jointly coordinate their signaling networks and are widely autoinhibited to remain sensitive to local activation. RhoGAPs exhibit lower substrate specificity than RhoGEFs and may contribute to preserving Rho activity gradients. Our approach led us to uncover a multi-RhoGEF complex downstream of G-protein-coupled receptors controlling a Cdc42/RhoA crosstalk. The spatial organization of Rho signaling thus differs from other small GTPases and expands the repertoire of mechanisms governing localized signaling activity.

cell biology↗

bioRxiv2017

The Fes tyrosine kinase guides CD19 receptor fate in B-cells by shaping regulatory Src phosphorylation networks

The c-Fes protein tyrosine kinase is a proto-oncogene that can also act as a tumor suppressor. We implemented an unbiased phosphoproteomics-based analysis that establishes cognate kinase-substrate associations, and revealed that c-Fes directly phosphorylates Dok1, Ptpn18 and Sts1, facilitating recruitment of the Src inhibitory kinase Csk to these substrates. These interactions resulted in modulation of Src signaling following B-cell receptor (BCR) stimulation and subsequent alteration of the protein levels of CD19, a membrane-localized BCR co-receptor and emerging key protein affecting the development of B- and plasma cell-lymphoma. Strikingly, manipulating c-Fes expression levels drove opposing biological outcomes. Low-level exogenous c-Fes expression led to a strong increase in CD19 protein levels while high c-Fes expression abolished CD19 protein levels. Thus, we propose that a balance of c-Fes and Src signaling can regulate receptor maintenance, which may influence cellular outcome such as tumorigenesis or tumor suppression.

systems biology↗