Biology subjects

Gona, S.

Publications and source records attributed to Gona, S..

5 recordsLinked to original sources

bioRxiv2024

scPrediXcan integrates advances in deep learning and single-cell data into a powerful cell-type-specific transcriptome-wide association study framework

Transcriptome-wide association studies (TWAS) help identify disease causing genes, but often fail to pinpoint disease mechanisms at the cellular level because of the limited sample sizes and sparsity of cell-type-specific expression data. Here we propose scPrediXcan which integrates state-of-the-art deep learning approaches that predict epigenetic features from DNA sequences with the canonical TWAS framework. Our prediction approach, ctPred, predicts cell-type-specific expression with high accuracy and captures complex gene regulatory grammar that linear models overlook. Applied to type 2 diabetes and systemic lupus erythematosus, scPrediXcan outperformed the canonical TWAS framework by identifying more candidate causal genes, explaining more genome-wide association studies (GWAS) loci, and providing insights into the cellular specificity of TWAS hits. Overall, our results demonstrate that scPrediXcan represents a significant advance, promising to deepen our understanding of the cellular mechanisms underlying complex diseases.

genetics↗

bioRxiv2023

An oxadiazole-based compound potentiates anti- tuberculosis treatment by increasing host resistance via zinc poisoning

Anti-tuberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multi-resistant strains of Mycobacterium tuberculosis are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, using high content imaging, we identified novel 1,2,4-oxadiazole-based compounds, that allow human macrophages to control MTB replication. Genome-wide gene expression analysis revealed that these molecules induced zinc remobilization inside cells, resulting in bacterial zinc intoxication. More importantly, we also demonstrated that, upon treatment with these novel compounds, M. tuberculosis became even more sensitive to anti-tuberculosis drugs, in vitro and in vivo, in a mouse model of tuberculosis. Manipulation of heavy metal homeostasis holds thus great promise to be exploited to develop host-directed therapeutic interventions.

microbiology↗

bioRxiv2022

Epigenetic variation impacts ancestry-associated differences in the transcriptional response to influenza infection

Humans display remarkable inter-individual variation in immune response when exposed to identical immune challenges. Yet, our understanding of the genetic and epigenetic factors contributing to such variation remains limited. Here we carried out in-depth genetic, epigenetic, and transcriptional profiling on primary macrophages derived from a panel of European and African-ancestry individuals before and after infection with influenza A virus (IAV). We show that baseline epigenetic profiles are strongly predictive of the transcriptional response to IAV across individuals, and that ancestry-associated differences in gene expression are tightly coupled with variation in enhancer activity. Quantitative trait locus (QTL) mapping revealed highly coordinated genetic effects on gene regulation with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. These data reveal that ancestry-associated differences in the epigenetic landscape are genetically controlled, even more so than variation in gene expression. Lastly, we show that among QTL variants that colocalized with immune-disease loci, only 7% were gene expression QTL, the remaining corresponding to genetic variants that impact one or more epigenetic marks, which stresses the importance of considering molecular phenotypes beyond gene expression in disease-focused studies.

genetics↗

bioRxiv2022

Transposable elements are associated with the variable response to influenza infection

Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Given that transposable elements (TEs) contribute to the activation of innate immunity, we wanted to explore their potential role in this variability. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using ATAC-seq we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators in stably enriched TE families and with other factors in variable families, including KRAB-ZNFs. We also observed a strong association between basal TE transcripts and viral load post infection. Finally, we built a predictive model suggesting that TEs, and host factors regulating TEs, contribute to the variable response to infection.

immunology↗

bioRxiv2021

GATA4 regionalizes intestinal metabolism and barrier function to prevent immunopathology

Different regions of the gastrointestinal tract have distinct digestive and absorptive functions, which may be locally disrupted by infection or autoimmune disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. Here, we used mouse models, transcriptomics, and immune profiling to show that regional epithelial expression of the transcription factor GATA4 prevented adherent bacterial colonization and inflammation in the proximal small intestine by regulating retinol metabolism and luminal IgA. Loss of epithelial GATA4 expression increased mortality in mice infected with Citrobacter rodentium. In active celiac patients with villous atrophy, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. This study reveals broad impacts of GATA4-regulated intestinal regionalization and highlights an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease. One-sentence summaryEpithelial GATA4 regulates intestinal regionalization of bacterial colonization, metabolic pathways, and tissue immunity.

immunology↗