Biology subjects

Chervontseva, Z.

Publications and source records attributed to Chervontseva, Z..

5 recordsLinked to original sources

bioRxiv2024

DREAMER: Exploring Common Mechanisms of Adverse Drug Reactions and Disease Phenotypes through Network-Based Analysis

Adverse drug reactions (ADRs) are a major concern in clinical healthcare, significantly affecting patient safety and drug development. The need for a deeper understanding of ADR mechanisms is crucial for improving drug safety profiles in drug design and drug repurposing. This study introduces DREAMER (Drug adverse REAction Mechanism ExplaineR), a novel network-based method for exploring the mechanisms underlying adverse drug reactions and disease phenotypes at a molecular level by leveraging a comprehensive knowledge graph obtained from various datasets. By considering drugs and diseases that cause similar phenotypes, and investigating their commonalities regarding their impact on specific modules of the protein-protein interaction network, DREAMER can robustly identify protein sets associated with the biological mechanisms underlying ADRs and unravel the causal relationships that contribute to the observed clinical outcomes. Applying DREAMER to 649 ADRs, we identified proteins associated with the mechanism of action for 67 ADRs across multiple organ systems, e.g., ventricular arrhythmia, metabolic acidosis, and interstitial pneumonitis. In particular, DREAMER highlights the importance of GABAergic signaling and proteins of the coagulation pathways for personality disorders and intracranial hemorrhage, respectively. We further demonstrate the application of DREAMER in drug repurposing and propose sotalol (targeting KCNH2), ranolazine (targeting SCN5A, currently under clinical trial), and diltiazem (indicated drug targeting CACNA1C and SCN3A) as candidate drugs to be repurposed for cardiac arrest. In summary, DREAMER effectively detects molecular mechanisms underlying phenotypes emphasizing the importance of network-based analyses with integrative data for enhancing drug safety and accelerating the discovery of novel therapeutic strategies.

systems biology↗

bioRxiv2021

A hierarchy in clusters of cephalopod mRNA editing sites

RNA editing in the form of substituting adenine to inosine (A-to-I editing) is the most frequent type of RNA editing, observed in many metazoan species. A-to-I editing sites form clusters in most studied species, and editing at clustered sites depends on editing of the adjacent sites. Although functionally important in some specific cases, A-to-I editing in most considered species is rare, the exception being soft-bodied cephalopods (coleoids), where tens of thousands of potentially important A-to-I editing sites have been identified, making coleoids an ideal object for studying of general properties and evolution of A-to-I editing sites. Here, we apply several diverse techniques to demonstrate a strong tendency of coleoid RNA editing sites to cluster along the transcript. We identify three distinct types of editing site clusters, varying in size, and describe RNA structural features and mechanisms likely underlying formation of these clusters. In particular, these observations may resolve the paradox of sequence conservation at large distances around editing sites.

bioinformatics↗

bioRxiv2020

Adaptive evolution at mRNA editing sites in soft-bodied cephalopods

The bulk of variability in mRNA sequence arises due to mutation - change in DNA sequence which is heritable if it occurs in the germline. However, variation in mRNA can also be achieved by post-translational modification including mRNA editing, changes in mRNA nucleotide sequence that mimic the effect of mutations. Such modifications are not inherited directly; however, as the processes affecting them are encoded in the genome, they have a heritable component, and therefore can be shaped by selection. In soft-bodied cephalopods, adenine-to-inosine RNA editing is very frequent, and much of it occurs at nonsynonymous sites, affecting the sequence of the encoded protein. Here, we show that mRNA editing of individual nonsynonymous sites in cephalopods originates in evolution through substitutions at regions adjacent to these sites. As such substitutions mimic the effect of the substitution at the edited site itself, we hypothesize that they are favored by selection if the inosine is selectively advantageous to adenine at the edited position. Consistent with this hypothesis and with observations on Drosophila and human editing sites, we show that edited adenines are more frequently substituted with guanine, an informational analogue of inosine, in the course of evolution than their unedited counterparts, and for heavily edited adenines, these transitions are favored by positive selection. Thus, our study shows that coleoid editing sites may enhance adaptation, which, together with distinct evolutionary features of Drosophila and human editing sites, points at a general role of RNA editing in the molecular evolution of metazoans.

evolutionary biology↗

bioRxiv2020

Identification of Differentially Expressed Gene Modules in Heterogeneous Diseases

MotivationIdentification of differentially expressed genes is necessary for unraveling disease pathogenesis. This task is complicated by the fact that many diseases are heterogeneous at the molecular level and samples representing distinct disease subtypes may demonstrate different patterns of dysregulation. Biclustering methods are capable of identifying genes that follow a similar expression pattern only in a subset of samples and hence can consider disease heterogeneity. However, identifying biologically significant and reproducible sets of genes and samples remains challenging for the existing tools. Many recent studies have shown that the integration of gene expression and protein interaction data improves the robustness of prediction and classification and advances biomarker discovery. ResultsHere we present DESMOND, a new method for identification of Differentially ExpreSsed gene MOdules iN Diseases. DESMOND performs network-constrained biclustering on gene expression data and identifies gene modules -- connected sets of genes up- or down-regulated in subsets of samples. We applied DESMOND on expression profiles of samples from two large breast cancer cohorts and have shown that the capability of DESMOND to incorporate protein interactions allows identifying the biologically meaningful gene and sample subsets and improves the reproducibility of the results. Availabilityhttps://github.com/ozolotareva/DESMOND Contactozolotareva@techfak.uni-bielefeld.de Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2019

Posttranscriptional regulation of ribosomal and multiresistance genes by the bacterial leader peptide peTrpL

The ribosome-dependent attenuator located upstream of bacterial tryptophan biosynthesis genes harbors a small ORF trpL containing tryptophan codons. When tryptophan is available, efficient trpL translation causes transcription termination and release of the attenuator RNA rnTrpL. In Sinorhizobium meliloti, rnTrpL is a trans-acting sRNA. Here, we identified an evolutionary conserved function for the trpL-encoded 14-aa leader peptide peTrpL. Upon exposure to tetracycline, the cellular peTrpL levels were increased and rnTrpL was generated independently of tryptophan availability. Both peTrpL and rnTrpL were found to be involved in tetracycline-dependent destabilization of rplUrpmA mRNA encoding ribosomal proteins L21 and L27. We provide evidence for redirection of the sRNA rnTrpL from its antibiotic-independent target trpDC to rplUrpmA by formation of an antibiotic-dependent ribonucleoprotein complex (ARNP). ARNPs comprising peTrpL, rnTrpL, rplUrpmA and antisense RNA were also observed for other translation-inhibiting antibiotics, suggesting that bacteria evolved mechanisms to utilize antibiotics for mRNA destabilization.

microbiology↗