Biology subjects

Piontkivska, H.

Publications and source records attributed to Piontkivska, H..

15 recordsLinked to original sources

bioRxiv2026

Sex-specific differences in ADAR editing patterns in response to SARS-CoV-2 infections

Sex-specific differences in COVID-19 outcomes are well documented, with male sex being a key risk factor for severe disease. Multiple factors, including differences in the expression of Interferons (IFNs) and Interferon stimulated genes (ISGs) between the sexes have been identified as contributing to these differences. Adenosine-to-inosine (A-to-I) RNA editing, mediated by ADAR enzymes, is an important component of antiviral innate immune signaling. While previous studies, including us, have identified altered expression and activity of ADARs in response to SARS-CoV-2 infection, it remains unknown whether sex-specific differences in expression and activity of ADARs exist during infection with SARS-CoV-2. We address this question by analyzing a publicly available whole blood RNA sequencing dataset from males and females, matched for age and comorbidity status across pre-, mid-, and post-infection stages of SARS-CoV-2 infection. Our results show distinct patterns of ADAR expression between the sexes across different stages of infection, with significant differences in the expression of ADAR and ADAR2 in pre- and mid- infection that were not observed post-viral clearance. Interestingly, expression of predominantly neural isoform ADAR3 was significantly different and higher in females, mid-infection. Furthermore, these differences in ADAR expression were likely amplified downstream with significant differences in the global editing levels. Correlation analysis revealed that the relationship between ADAR expression and global editing activity differed by sex and stage of infection, indicating that ADAR editing is dynamically regulated and is influenced by factors other than ADAR transcript abundance. Noteworthy, sex-specific differences in ADAR editing were observed within genes that escape X-chromosome inactivation (XCI), a gene set enriched in immune related functions and known to be involved in sex-specific outcomes to viral infections. ADAR editing within these genes differed at baseline and changed across stages of infection in a manner independent of gene expression. Altogether, our findings establish ADAR editing as an additional layer of immune regulation that may be contributing, in part, to the differential clinical manifestations of COVID-19 observed between males and females.

bioinformatics↗

bioRxiv2026

Fluoxetine Hydrochloride Treatment Influences Site-Specific ADAR Editing and Transcriptome Regulation in Arid1b +/- Mice

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behavior and impaired social interactions. Recent reports from human postmortem brain samples of ASD show transcriptome-wide dysregulations, including changes in differential gene expression and alternative splicing. An important mechanism regulating transcriptome function is the editing of double-stranded RNA by adenosine deaminases acting on RNA (ADARs), which play regulatory roles in neurodevelopment and innate immunity. We explore the ADAR editing changes associated with the use of Selective Serotonin Reuptake Inhibitors (SSRIs) in Arid1b haploinsufficient mouse models. Our results show dynamic changes in site-specific editing rates in autistic mice. We further demonstrate the transcriptome-wide effects of differential ADAR editing in terms of changes in miRNA-mRNA interactions. Moreover, our findings highlight a site-specific change in editing rates for evolutionarily conserved sites in mammals and ASD associated risk genes, such as Gria2. Our analysis of significant biological processes shows the association of differentially edited genes with processes vital for neurotransmission. Overall, our findings imply that the use of SSRIs can induce distinct ADAR editing signatures, potentially contributing to ASD pathology.

bioinformatics↗

bioRxiv2025

SARS-CoV-2 infection induced alterations in ADAR editing patterns differ between patients who developed critical compared to non-critical COVID-19

COVID-19, caused by the SARS-CoV-2 virus, has a wide spectrum of clinical presentations even among individuals with similar demographics. Disease severity has been linked with viral recognition-triggered expression of Interferons (IFNs) and Interferon stimulated genes (ISGs). Among these ISGs, ADARp150 is a member of adenosine deaminases acting on RNA (ADARs) enzyme family. ADARs are RNA editing enzymes that contribute to transcriptome diversity and modulate immune response during viral infections. While previous studies have identified altered ADAR expression and editing patterns during SARS-CoV-2 infection, it remains unknown whether ADAR expression and activity differ between patients with varying severities of COVID-19, specifically, in individuals who developed critical compared to non-critical COVID-19. We address this question by analyzing a publicly available, deeply sequenced whole blood RNA-seq dataset from individuals with either critical or non-critical COVID-19, matched for age, sex, and presence of comorbidities. Our results show differential expression of thousands of genes, including those involved in neutrophil degranulation, and upregulation of ADAR1 and its isoform ADARp110 in patients with critical COVID-19. We further identify global differences in the total number of edits, driven by ADAR1 and ADAR2 expression levels in critical but not in non-critical patients. ADAR activity also differed within Alu elements and in the proportion of edits with varying functional consequences. We further identified severity specific editing events, including nonsynonymous edits, within distinct biological pathways. Moreover, we identified 140 high confidence editing sites within 126 genes, that are differentially edited between the two patient groups. These genes were enriched in infectious disease, cell cycle, signal transduction, RNA and protein metabolism in addition to inflammatory pathways such as neutrophil degranulation and signaling by interleukins. Enrichment/modulation of neutrophil degranulation pathway at transcriptional and post transcriptional levels suggest the importance, complex regulation, and contribution of this pathway in COVID-19 disease severity. Finally, using a random forest classifier, we identified a set of differentially edited sites that could serve as molecular markers for COVID-19 disease severity. Together, our study demonstrates varying expression and editing patterns of ADARs between critical and non-critical patients, suggesting a potential role of ADAR editing in varying severity of COVID-19 pathogenesis.

bioinformatics↗

bioRxiv2025

Unraveling Hypoxia Tolerance: Transcriptomic and Metabolic Insights from Lucinoma capensis in an Oxygen Minimum Zone

The lucinid clam Lucinoma capensis thrives at the oxygen minimum zone margins in the Benguela Upwelling System, where oxygen levels fluctuate dramatically. Understanding its adaptation to such extreme conditions provides key insights into survival strategies under fluctuating oxygen availability. We investigated the transcriptomic and metabolomic responses of L. capensis under normoxia, hypoxia, and recovery, focusing on the gills and digestive gland. Our findings highlight distinct organ-specific responses, with the gills showing strong transcriptional changes to oxygen fluctuations, in contrast to the more stable profile observed in the digestive gland. Under hypoxic conditions, the gills exhibited coordinated downregulation of critical metabolic processes, including protein synthesis, transposable element activity, and immune function, suggesting a tightly regulated energy conservation strategy and mechanisms to preserve symbiont stability and genomic integrity. Activation of prokaryotic metabolism in the gills supports the symbionts role in host energy acquisition and sulfide detoxification during hypoxia. In contrast, the digestive gland showed minimal transcriptional shifts during anoxia, with upregulation of pathways supporting structural maintenance. Upon reoxygenation, the gills displayed an active and asymmetric recovery, characterized by rapid restoration of protein synthesis and gradual normalization of protein degradation and immune functions. Despite significant transcriptomic changes, the metabolome remained largely stable, reflecting L. capensiss resilience to oxygen fluctuations. However, an overshoot in TCA cycle intermediates and derepression of previously downregulated pathways indicate that reoxygenation involves active metabolic reprogramming, not merely a return to baseline. This study highlights the specialized tissue responses and symbiotic contributions that enable L. capensis to thrive in one of the oceans most challenging environments.

physiology↗

bioRxiv2025

SARS-CoV-2-induced dysregulation in ADAR editing patterns persists post viral clearance in individuals with mild COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections remain a public health concern worldwide. Viral antigen triggered innate immune response leads to induction of interferons (IFNs) and interferon stimulated genes (ISGs) including ADAR1 p150 isoform, which edits adenosine (A) residues within double stranded RNAs in both the virus and the host. Such RNA editing mediated by ADARs plays a crucial role in innate immune responses during viral infections through modulation of host-virus interactions. Additionally, ADAR editing acts post-transcriptionally, and serves as a mechanism of dynamic regulation of transcriptome and proteome diversity. While evidence points to changes in ADAR editing during infection, we do not know whether editing targets change over the course of the infection. Here, we explored temporal changes in ADAR expression and editing patterns, across three distinct stages of SARS-CoV-2 infection. Furthermore, we examined whether infection-triggered dysregulation in ADAR editing persists or returns to pre-infection states post-viral clearance. We addressed this question by analyzing publicly available whole blood RNA sequencing samples from forty-five, age-matched individuals. The individuals selected had no documented comorbidities, developed mild COVID-19, and were sampled across three distinct stages of SARS-CoV-2 infection: pre-, mid-, and post-infection. Our results demonstrate dynamic changes in ADAR expression and editing across the three stages. We further identified unique editing sites resulting from SARS-CoV-2 infection, across all three stages of infection, within genes involved in immune response pathways. Noteworthy, genes within neutrophil degranulation pathway appear to be edited, suggesting they may play a role in inflammation and sequelae observed post-SARS-CoV-2 infection. Our results demonstrate a consistent trend of elevated ADAR expression and reduced overall ADAR editing within each individual mid-infection. Subsequently, in some post-infection samples ADAR expression returns to approximately pre-infection levels, while in others it remains dysregulated. These differences may be contributing to heterogeneity in disease outcomes seen in individuals post-SARS-CoV-2 infection.

bioinformatics↗

bioRxiv2024

The role of ADAR editing and nonsense-mediated decay in Parkinson's Disease

Parkinsons Disease (PD) is a multifactorial disease with heterogenous phenotypes that vary across individuals, as well as by age and sex. Therefore, it is likely that multiple interacting factors, such as environmental influences and aging, as well as genetic factors, including dynamic RNA (ADAR, Adenosine Deaminases Acting on RNA) editing, may play a role in PD pathology. In this analysis of 317 transcriptomes of healthy controls, PD and prodromal patients aged 65 years or older, from Parkinsons Project Markers Initiative dataset, we observe differences in ADAR expression, number of putative ADAR edits, editing index, and the number of high and moderate impact edits between control groups and diseased samples, particularly when ADAR editing is associated with nonsense-mediated decay (NMD). Likewise, differentially expressed genes between comparison groups were linked to NMD-related pathways. NMD is an important process in detecting deleterious nonsense sequences in mRNA transcripts and eliminating them from the cell. Thus, NMD regulation serves an important role in neurodevelopment, neural differentiation, and neural maturation. RNA misprocessing, which includes dysregulation of NMD, is known to play an important role in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. Our results suggest that NMD may also be an important factor in PD physiology.

bioinformatics↗

bioRxiv2024

Reovirus infection induces transcriptome-wide unique A-to-I editing changes in the murine fibroblasts

The conversion of Adenosine (A) to Inosine (I), by Adenosine Deaminases Acting on RNA or ADARs, is an essential post-transcriptional modification that contributes to proteome diversity and regulation in metazoans including humans. In addition to its transcriptome-regulating role, ADARs also play a major part in immune response to viral infection, where an interferon response activates interferon-stimulated genes, such as ADARp150, in turn dynamically regulating host-virus interactions. A previous report has shown that infection from reoviruses, despite strong activation of ADARp150, does not influence the editing of some of the major known editing targets, while likely editing others, suggesting a potentially nuanced editing pattern that may depend on different factors. However, the results were based on a handful of selected editing sites and did not cover the entire transcriptome. Thus, to determine whether and how reovirus infection specifically affects host ADAR editing patterns, we analyzed a publicly available deep-sequenced RNA-seq dataset, from murine fibroblasts infected with wild-type and mutant reovirus strains that allowed us to examine changes in editing patterns on a transcriptome-wide scale. To the best of our knowledge, this is the first transcriptome-wide report on host editing changes after reovirus infection. Our results demonstrate that reovirus infection induces unique nuanced editing changes in the host, including introducing sites uniquely edited in infected samples. Genes with edited sites are overrepresented in pathways related to immune regulation, cellular signaling, metabolism, and growth. Moreover, a shift in editing targets has also been observed, where the same genes are edited in infection and control conditions but at different sites, or where the editing rate is increased for some and decreased for other differential targets, supporting the hypothesis of dynamic and condition-specific editing by ADARs.

bioinformatics↗

bioRxiv2023

The LH receptor regulates hippocampal spatial memory and restores dendritic spine density in ovariectomized APP/PS1 AD mice

Activation of the luteinizing hormone receptor (LHCGR) rescues spatial memory function and spine density losses associated with gonadectomy and high circulating gonadotropin levels in females. However, whether this extends to the AD brain or the mechanisms that underlie these benefits remain unknown. To address this question, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV), under reproductively intact and ovariectomized conditions to mimic the post-menopausal state in the APP/PS1mouse brain. Cognitive function was tested using the Morris water maze task, and hippocampal dendritic spine density, A{beta} pathology, and signaling changes associated with these endpoints were determined to address mechanisms. Here we show that central LHCGR activation restored function in ovariectomized APP/PS1 female mice to wild-type levels without altering A{beta} pathology. LHCGR activation increased hippocampal dendritic spine density regardless of reproductive status, and this was mediated by BDNF-dependent and independent signaling. We also show that ovariectomy in the APP/PS1 brain elicits an increase in peripherally derived pro-inflammatory genes which are inhibited by LHCGR activation. This may mediate reproductive status specific effects of LHCGR agonism on cognitive function and BDNF expression. Together, this work highlights the relevance of the LHCGR on cognition and its therapeutic potential in the "menopausal" AD brain.

neuroscience↗

bioRxiv2023

Changes in ADAR RNA Editing Patterns in CMV and ZIKV Congenital Infections

BackgroundRNA editing is a process that increases transcriptome diversity, often through Adenosine Deaminases Acting on RNA (ADARs) that catalyze the deamination of adenosine to inosine. ADAR editing plays an important role in regulating brain function and immune activation, and is dynamically regulated during brain development. Additionally, the ADAR1 p150 isoform is induced by interferons in viral infection and plays a role in antiviral immune response. However, the question of how virus-induced ADAR expression affects host transcriptome editing remains largely unanswered. This question is particularly relevant in the context of congenital infections, given the dynamic regulation of ADAR editing during brain development, the importance of this editing for brain function, and subsequent neurological symptoms of such infections, including microcephaly, sensory issues, and other neurodevelopmental abnormalities. Here, we begin to address this question, examining ADAR expression in publicly available datasets of congenital infections of human cytomegalovirus (HCMV) microarray expression data, as well as mouse cytomegalovirus (MCMV) and mouse/ human induced pluripotent neuroprogenitor stem cell (hiNPC) Zika virus (ZIKV) RNA-seq data. ResultsWe found that in all three datasets, ADAR1 was overexpressed in infected samples compared to uninfected samples. In the RNA-seq datasets, editing rates were also analyzed. In all mouse infections cases, the number of editing sites was significantly increased in infected samples, albeit this was not the case for hiNPC ZIKV samples. Mouse ZIKV samples showed altered editing of well-established protein-recoding sites such as Gria3, Grik5, and Nova1, as well as editing sites that may impact miRNA binding. ConclusionsOur findings provide evidence for changes in ADAR expression and subsequent dysregulation of ADAR editing of host transcriptomes in congenital infections. These changes in editing patterns of key neural genes have potential significance in the development of neurological symptoms, thus contributing to neurodevelopmental abnormalities. Further experiments should be performed to explore the full range of editing changes that occur in different congenital infections, and to confirm the specific functional consequences of these editing changes.

bioinformatics↗

bioRxiv2023

Alterations in RNA editing in skeletal muscle following exercise training in individuals with Parkinsons disease

Parkinsons Disease (PD) is the second most common neurodegenerative disease behind Alzheimers Disease, currently affecting more than 10 million people worldwide and 1.5 times more males than females. The progression of PD results in the loss of function due to neurodegeneration and neuroinflammation. The etiology of PD is multifactorial, including both genetic and environmental origins. Here we explored changes in RNA editing, specifically editing through the actions of the Adenosine Deaminases Acting on RNA (ADARs), in the progression of PD. Analysis of ADAR editing of skeletal muscle transcriptomes from PD patients and controls, including those that engaged in a rehabilitative exercise training program revealed significant differences in ADAR editing patterns based on age, disease status, and following rehabilitative exercise. Further, deleterious editing events in protein coding regions were identified in multiple genes with known associations to PD pathogenesis. Our findings of differential ADAR editing complement findings of changes in transcriptional network identified by a recent Lavin et al. (2020) study and offer insights into dynamic ADAR editing changes associated with PD pathogenesis.

bioinformatics↗

bioRxiv2021

Differential ADAR editing landscapes in major depressive disorder and suicide

Neuropsychiatric disorders, including depression and suicide, are becoming an increasing public health concern. Rising rates of both depression and suicide, exacerbated by the current COVID19 pandemic, have only hastened our need for objective and reliable diagnostic biomarkers. These can aide clinicians treating depressive disorders in both diagnosing and developing treatment plans. While differential gene expression analysis has highlighted the serotonin signaling cascade among other critical neurotransmitter pathways to underly the pathology of depression and suicide, the biological mechanisms remain elusive. Here we propose a novel approach to better understand molecular underpinnings of neuropsychiatric disorders by examining patterns of differential RNA editing by adenosine deaminases acting on RNA (ADARs). We take advantage of publicly available RNA-seq datasets to map ADAR editing landscapes in a global gene-centric view. We use a unique combination of Guttman scaling and random forest classification modeling to create, describe and compare ADAR editing profiles focusing on both spatial and biological sex differences. We use a subset of experimentally confirmed ADAR editing sites located in known protein coding regions, the excitome, to map ADAR editing profiles in Major Depressive Disorder (MDD) and suicide. Using Guttman scaling, we were able to describe significant changes in editing profiles across brain regions in males and females with respect to cause of death (COD) and MDD diagnosis. The spatial distribution of editing sites may provide insight into biological mechanisms under-pinning clinical symptoms associated with MDD and suicidal behavior. Additionally, we use random forest modeling including these differential profiles among other markers of global editing patterns in order to highlight potential biomarkers that offer insights into molecular changes underlying synaptic plasticity. Together, these models identify potential prognostic, diagnostic and therapeutic biomarkers for MDD diagnosis and/or suicide.

bioinformatics↗

bioRxiv2021

Genomic evolution of epitopes and low complexity regions in Plasmodium

Despite decades-long efforts to eradicate malaria, pathogens genomic complexity and variability continue to pose major challenges for the vaccine and drug development. Here we examined the evolutionary history of epitopes and epitope-like regions to determine whether they share underlying evolutionary mechanisms and potential functions that are relevant to pathogens interactions with the host immune response. Our comparative sequence analyses contrasted patterns of sequence conservation, amino acid composition, and protein structure of epitopes and low complexity regions (LCRs) in 21 Plasmodium species. Our results revealed many similarities in amino acid composition and preferred secondary structures between epitopes and LCRs; however, we also identified differences in evolutionary trends where LCRs exhibit overall lower sequence conservation and higher disorder. We also found that both epitopes and LCRs have a wide array of configurations, with various levels of sequence conservation and structural order. We propose that such combination of different levels of conservation and structural order between epitopes and LCRs in the same gene play a role in maintaining the functional integrity required by the pathogen along with the variability necessary to evade the host immune response, with LCRs playing a role in the evasion particularly in the vicinity of conserved epitopes. Overall, our results suggest that there are at least two categories of LCRs, where some LCRs play a potential protective role for conserved (ordered) epitopes because of their variable (or disordered) sequence, while others are less disordered and are as conserved as epitopes. The former ones may be an evolutionary necessity for Plasmodium to maintain the diversity of epitopes, while the latter category may serve currently unknown function(s) and deserve to be examined in greater detail. Our findings show that there may be many more candidate targets for future anti-malarial treatments than initially thought and that some of these targets may work across strains and species.

evolutionary biology↗

bioRxiv2020

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, primate-specific isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In vitro, dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results reconcile current knowledge on ACE2 expression and suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, inflammatory tumor microenvironment, or viral co-infections is unlikely to affect the cellular entry of SARS-CoV-2 and promote infection.

genetics↗

bioRxiv2020

Machine Learning Maps Research Needs in COVID-19 Literature

SummaryManually assessing the scope of the thousands of publications on the COVID-19 (coronavirus disease 2019) pandemic is an overwhelming task. Shortcuts through metadata analysis (e.g., keywords) assume that studies are properly tagged. However, machine learning approaches can rapidly survey the actual text of coronavirus abstracts to identify research overlap between COVID-19 and other coronavirus diseases, research hotspots, and areas warranting exploration. We propose a fast, scalable, and reusable framework to parse novel disease literature. When applied to the COVID-19 Open Research Dataset (CORD-19), dimensionality reduction suggested that COVID-19 studies to date are primarily clinical-, modeling- or field-based, in contrast to the vast quantity of laboratory-driven research for other (non-COVID-19) coronavirus diseases. Topic modeling also indicated that COVID-19 publications have thus far focused primarily on public health, outbreak reporting, clinical care, and testing for coronaviruses, as opposed to the more limited number focused on basic microbiology, including pathogenesis and transmission.

scientific communication and education↗

bioRxiv2020

Automated Isoform Diversity Detector (AIDD): A pipeline for investigating transcriptome diversity of RNA-seq data

BackgroundAs the number of RNA-seq datasets that become available to explore transcriptome diversity increases, so does the need for easy-to-use comprehensive computational workflows. Many available tools facilitate analyses of one of the two major mechanisms of transcriptome diversity, namely, differential expression of isoforms due to alternative splicing, while the second major mechanism - RNA editing due to post-transcriptional changes of individual nucleotides - remains under-appreciated. Both these mechanisms play an essential role in physiological and diseases processes, including cancer and neurological disorders. However, elucidation of RNA editing events at transcriptome-wide level requires increasingly complex computational tools, in turn resulting in a steep entrance barrier for labs who are interested in high-throughput variant calling applications on a large scale but lack the manpower and/or computational expertise. ResultsHere we present an easy-to-use, fully automated, computational pipeline (Automated Isoform Diversity Detector, AIDD) that contains open source tools for various tasks needed to map transcriptome diversity, including RNA editing events. To facilitate reproducibility and avoid system dependencies, the pipeline is contained within a pre-configured VirtualBox environment. The analytical tasks and format conversions are accomplished via a set of automated scripts that enable the user to go from a set of raw data, such as fastq files, to publication-ready results and figures in one step. A publicly available dataset of Zika virus-infected neural progenitor cells is used to illustrate AIDDs capabilities. ConclusionsAIDD pipeline offers a user-friendly interface for comprehensive and reproducible RNA-seq analyses. Among unique features of AIDD are its ability to infer RNA editing patterns, including ADAR editing, and inclusion of Guttman scale patterns for time series analysis of such editing landscapes. AIDD-based results show importance of diversity of ADAR isoforms, key RNA editing enzymes linked with the innate immune system and viral infections. These findings offer insights into the potential role of ADAR editing dysregulation in the disease mechanisms, including those of congenital Zika syndrome. Because of its automated all-inclusive features, AIDD pipeline enables even a novice user to easily explore common mechanisms of transcriptome diversity, including RNA editing landscapes.

bioinformatics↗