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

Ja, Resztak; Jiang, Wei; Zilioli, Samuele; Sendler, Edward; Alazizi, Adnan; He, Mair-Meijers; Wu, Peng; Rb, Slatcher; Zhou, Xiaofeng; Luca, Francesca; Piqué-Regi, Roger

doi:10.1101/2021.09.30.462672

Cited by 6 publications

(19 citation statements)

References 173 publications

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“…Over the past ten years, there has been an increased appreciation for the degree to which eQTL may be context specific, starting first with tissue type, then to functional/environmental context, and finally to cell type [30][31][32][33][34][35][36][37] . The results of this study suggest single cell eQTL studies have the power to more robustly elucidate this context specificity, and that they will better recover eQTL associated with disease states or environmental perturbations as these effects are less likely to be shared across cell type within a tissue.…”

Section: Discussionmentioning

confidence: 99%

Cell type-specific and disease-associated eQTL in the human lung

Natri

Azodi

Peter

et al. 2023

Preprint

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Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis (PF). Defining the genetic control of gene expression in a cell-type-specific and context-dependent manner is critical for understanding the mechanisms through which genetic variation influences complex traits and disease pathobiology. To this end, we performed single-cell RNA-sequencing of lung tissue from 67 PF and 49 unaffected donors. Employing a pseudo-bulk approach, we mapped expression quantitative trait loci (eQTL) across 38 cell types, observing both shared and cell type-specific regulatory effects. Further, we identified disease-interaction eQTL and demonstrated that this class of associations is more likely to be cell-type specific and linked to cellular dysregulation in PF. Finally, we connected PF risk variants to their regulatory targets in disease-relevant cell types. These results indicate that cellular context determines the impact of genetic variation on gene expression, and implicates context-specific eQTL as key regulators of lung homeostasis and disease.

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Section: Discussionmentioning

confidence: 99%

Cell type-specific and disease-associated eQTL in the human lung

Natri

Azodi

Peter

et al. 2023

Preprint

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“…Monocytes are one of the cell types in PBMCs and single cell studies have shown that their transcriptional status influences other PBMC components (e.g. T cells) 56,57 . Lack of plasticity of monocytes/macrophages in the inflammatory to anti-inflammatory signaling promotes ineffective wound healing, which is a main complication of type 2 Diabetes 58 .…”

Section: Discussionmentioning

confidence: 99%

Poverty shapes the transcriptome of immune cells

Arnold

Resztak

Alazizi

et al. 2022

Preprint

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Social determinants of health influence health outcomes and life expectancy. Specifically, individuals living in poverty often have adverse health outcomes related to chronic inflammation that affect the cardiovascular, renal, and pulmonary systems. However, the underlying mechanisms by which poverty increases the risk of disease and health disparities are still not fully understood. To bridge the gap in our understanding of the link between living in poverty and adverse health outcomes, we performed RNA sequencing of blood immune cells from 204 participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study in Baltimore City, Maryland. This study cohort included men and women self-identified as African American and White. We identified 581 genes differentially expressed in association with poverty. A larger number of differentially expressed genes were detected in women, compared to men, and 64 genes had distinct sex-by-poverty interaction effects. Genes differentially expressed in women living in poverty were enriched in wound healing and coagulation processes, while in men were mostly related to immunoglobulin production and humoral immune response. Of the genes differentially expressed in individuals living in poverty, 275 are also associated with complex diseases in transcriptome-wide association studies. Our results suggest that living in poverty influences inflammation and the risk for chronic disease through gene expression changes in immune cells, and that some of the effects of living in poverty are different in women and men.

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“…To this end, we considered all peaks that were assigned to a gene as described above, and calculated the median LFC. The LFC values of transcriptional levels and variability were obtained from our previous scRNA-seq study (Resztak et al (2023)).…”

Section: Differential Accessibility Analysismentioning

confidence: 99%

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

Wei,

Resztak,

Alazizi

et al. 2023

Preprint

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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 environ-mental 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 children with asthma with phytohemagglutinin (PHA) or lipopolysaccharide (LPS), and treated with dexamethasone (DEX), an anti-inflammatory 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 in-crease 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 highly enriched in peaks with response motifs and refined the credible set of several asthma risk genes. In conclusion, scATAC-seq enhances the understanding of molecular mechanisms for asthma risk variants mediated by gene expression.

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

Cited by 6 publications

References 173 publications

Cell type-specific and disease-associated eQTL in the human lung

Cell type-specific and disease-associated eQTL in the human lung

Poverty shapes the transcriptome of immune cells

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

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