Biology subjects

Zilioli, S.

Publications and source records attributed to Zilioli, S..

5 recordsLinked to original sources

bioRxiv2025

Psychological stress and social support are associated with opposing single-cell pro-inflammatory gene regulatory mechanisms in adults

Psychological stress is linked to elevated markers of chronic inflammation, whereas social support is associated with lower levels; yet, the molecular mechanisms mediating these effects are poorly understood. We investigated gene regulatory variation in peripheral blood mononuclear cells (PBMCs) from 165 self-reported African American adults (aged 50-89 years) using single-cell RNA sequencing (scRNA-seq) and single-cell chromatin accessibility (scATAC-seq). Self-reported psychological stress and social support were associated with differential expression of 1,956 and 1,296 genes, respectively (10% FDR), primarily in CD4+ T cells and monocytes. Interferon signaling genes showed high expression in individuals with high psychological stress and low expression in those with high social support; this pattern mirrored gene expression in individuals with elevated circulating inflammatory markers (IFN-{gamma}, TNF-, IL-6). Genome-wide transcription factor (TF) motif analysis identified stress- and social support-associated changes in motif activity for 70 and 116 TFs, respectively, with 87 motifs enriched near differentially expressed genes. In CD4+ T cells, high psychological stress corresponded to increased IRF and STAT TF motif activity (interferon pathway), while social support was associated with reduced activity and expression in these pathways. We used an immune challenge paradigm (i.e., LPS stimulation), which confirmed the biological pathways of these gene regulatory effects. Our results demonstrate that psychological stress and social support modulate immune gene regulation at the single-cell level, revealing mechanistic links between psychosocial factors and inflammation, and suggesting that social support may promote immunological health.

genomics↗

bioRxiv2023

Functional characterization of eQTLs and asthma risk loci with scATAC-seq across immune cell types and contexts

Cis-regulatory elements (CREs) control gene transcription dynamics across cell types and in response to the environment. In asthma, multiple immune cell types play an important role in the inflammatory process. Genetic variants in CREs can also affect gene expression response dynamics and contribute to asthma risk. However, the regulatory mechanisms underlying control of transcriptional dynamics across different environmental contexts and cell-types at single cell resolution remains to be elucidated. To resolve this question, we performed scATAC-seq in activated peripheral blood mononuclear cells (PBMC) from 16 children with asthma with phytohemagglutinin (PHA) or lipopolysaccharide (LPS), and treated with dexamethasone (DEX), an antiinflammatory glucocorticoid. We analyzed changes in chromatin accessibility, measured transcription factor motif activity, and identified treatment and cell-type specific transcription factors that drive changes in both gene expression mean and variability. We observed strong positive linear dependence between motif response and their target gene expression changes, but negative in variability changes. This result suggests that an increase of transcription factor binding tightens the variability of gene expression around the mean. We then annotated genetic variants in chromatin accessibility peaks and response motifs followed by computational fine-mapping of eQTL signals from a pediatric asthma cohort. We found that eQTLs were 5-fold enriched in peaks with response motifs and refined the credible set for 410 asthma risk genes, with 191 having the causal variant in response motifs. In conclusion, scATAC-seq enhances the understanding of molecular mechanisms for asthma risk variants mediated by gene expression.

genomics↗

bioRxiv2021

Analysis of transcriptional changes associated with pubertal development

Puberty is an important developmental period marked by hormonal, metabolic and immune changes. Puberty also marks a shift in sex differences in susceptibility to asthma. Yet, little is known about the gene expression changes in immune cells that occur during pubertal development. Here we assess pubertal development and leukocyte gene expression in a longitudinal cohort of 251 children with asthma. We identify substantial gene expression changes associated with age and pubertal development. Gene expression changes between pre- and post-menarcheal females suggest a shift from predominantly innate to adaptive immunity. We show that genetic effects on gene expression change dynamically during pubertal development. Gene expression changes during puberty are correlated with gene expression changes associated with asthma and may explain sex differences in prevalence. Our results show that molecular data used to study the genetics of early onset diseases should consider pubertal development as an important factor that modifies the transcriptome.

genomics↗

bioRxiv2021

Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single cell resolution

Synthetic glucocorticoids, such as dexamethasone, have been used as treatment for many immune conditions, such as asthma and more recently severe COVID-19. Single cell data can capture more fine-grained details on transcriptional variability and dynamics to gain a better understanding of the molecular underpinnings of inter-individual variation in drug response. Here, we used single cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated Peripheral Blood Mononuclear Cells from 96 African American children. We employed novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we demonstrated that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and demonstrated widespread genetic regulation of the transcriptional dynamics of the gene expression response.

genomics↗

bioRxiv2020

Psychosocial experiences modulate asthma-associated genes through gene-environment interactions

Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here we investigated the effect of psychosocial experiences on gene expression in peripheral blood immune cells of children with asthma in Metro Detroit. Using RNA-sequencing and a new machine learning approach, we identified transcriptional signatures of 20 variables including psychosocial factors, blood cell composition and asthma symptoms. Importantly, we found 174 genes associated with asthma that are regulated by psychosocial factors, and 349 significant gene-environment interactions for gene expression levels. These results demonstrate that immune gene expression mediates the link between negative psychosocial experiences and asthma risk.

genomics↗