Biology subjects

Wicik, Z.

Publications and source records attributed to Wicik, Z..

2 recordsLinked to original sources

bioRxiv2020

ACE2 interaction networks in COVID-19: a physiological framework for prediction of outcome in patients with cardiovascular risk factors

(1) BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019; COVID-19) is associated with adverse outcomes in patients with cardiovascular disease (CVD). The aim of the study was to characterize the interaction between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) functional networks with a focus on CVD.; (2) MethodsUsing the network medicine approach and publicly available datasets, we investigated ACE2 tissue expression and described ACE2 interaction networks which could be affected by SARS-CoV-2 infection in the heart, lungs and nervous system. We compared them with changes in ACE-2 networks following SARS-CoV-2 infection by analyzing public data of stem cell-derived cardiomyocytes (hiPSC-CMs). This analysis was performed using the NERI algorithm, which integrates protein-protein interaction with co-expression networks. We also performed miRNA-target predictions to identify which ones regulate ACE2-related networks and could play a role in the COVID19 outcome. Finally, we performed enrichment analysis for identifying the main COVID-19 risk groups. (3) ResultsWe found similar ACE2 expression confidence levels in respiratory and cardiovascular systems, supporting that heart tissue is a potential target of SARS-CoV-2. Analysis of ACE2 interaction networks in infected hiPSC-CMs identified multiple hub genes with corrupted signalling which can be responsible for cardiovascular symptoms. The most affected genes were EGFR, FN1, TP53, HSP90AA1, and APP, while the most affected interactions were associated with MAST2 and CALM1. Enrichment analysis revealed multiple diseases associated with the interaction networks of ACE2, especially cancerous diseases, obesity, hypertensive disease, Alzheimers disease, non-insulin-dependent diabetes mellitus, and congestive heart failure. Among affected ACE2-network components connected with SARS-Cov-2 interactome, we identified AGT, CAT, DPP4, CCL2, TFRC and CAV1, associated with cardiovascular risk factors. We described for the first time miRNAs which were common regulators of ACE2 networks and virus-related proteins in all analyzed datasets. The top miRNAs were miR-27a-3p, miR-26b-5p, miR-10b-5p, miR-302c-5p, hsa-miR-587, hsa-miR-1305, hsa-miR-200b-3p, hsa-miR-124-3p, and hsa-miR-16-5p.; (4) ConclusionOur study provides a complete mechanistic framework for investigating the ACE2 network which was validated by expression data. This framework predicted risk groups, including the established ones, thus providing reliable novel information regarding the complexity of signalling pathways affected by SARS-CoV-2. It also identified miR which could be used in personalized diagnosis in COVID-19.

genomics↗

bioRxiv2017

Intragenomic Redistribution Of Host Transcription Factor Binding With Toxoplasma gondii Infection

The intracellular pathogen Toxoplasma gondii modifies a number of host cell processes. The mechanisms by which T. gondii alters host gene expression are incompletely understood. This study focuses on how the regulators of gene expression in human host cells respond to T. gondii 24 hours following infection to cause specific patterns of transcriptional dysregulation. The most striking finding was the altered landscape of transposase-accessible chromatin by infection. We found both gains and losses of loci of open chromatin enriched in proximity to transcriptionally altered genes. Both DNA sequence motif analysis at the loci changing chromatin accessibility and network analysis of the genes with transcription and regulatory changes implicate a central role for the AP-1 transcription factor. We validated the redistribution of AP-1 in the host genome using chromatin immunoprecipitation studies of the c-Fos component of AP-1. As infection with T. gondii is associated with the cell failing to progress through the cell cycle, all of the changes observed occur in the absence of cell division and within 24 hours, an insight into the dynamism of these transcriptional regulatory events. We conclude that T. gondii infection influences transcriptional regulation through transcription factor re-targeting to modify the cis-regulatory landscape of the host nucleus.\n\nAUTHOR SUMMARYThe complex interactions between the intracellular pathogen Toxoplasma gondii and the host cell manifest as expression changes of host genes. T. gondiis secreted effectors have been extensively studied and include factors that influence the properties of transcription factors, resulting in post-translational modifications and changes in intracellular localization. To gain insights into how T. gondii exerts specific influences on host transcriptional regulation, we used genome-wide approaches to study gene expression, cytosine modifications, and chromatin structure of the host cell 24 hours after infection. The greatest insights were gained from the mapping of loci of transposase-accessible chromatin, revealing a consistently altered pattern of a subset of loci becoming inaccessible, with the simultaneous acquisition of a new set of infection-associated loci of open chromatin. The sequences at these loci were enriched for certain transcription factor binding motifs, in particular that of AP-1, the transcription factor formed by c-Jun and c-Fos heterodimers. Network analysis revealed a central role for c-Jun and c-Fos in the infection-associated perturbations, prompting a chromatin immunoprecipitation approach that confirmed the redistribution of c-Fos in infected cells. We conclude that a T. gondii infection leads to an intragenomic redistribution of host transcription factor binding, with resulting effects on host gene expression.

genomics↗