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 a 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 used novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we showed 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 showed widespread genetic regulation of the transcriptional dynamics of the gene expression response.

Analysis of transcriptional changes in the immune system associated with pubertal development in a longitudinal cohort of children with asthma.

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.

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.

Socioeconomic status, financial stress, and glucocorticoid resistance among youth with asthma: Testing the moderation effects of maternal involvement and warmth.

OBJECTIVES: Children who grow up in more socioeconomically disadvantaged homes experience greater levels of inflammation and worse asthma symptoms than children from more advantaged families. However, recent evidence suggests that certain family-level factors can mitigate health disparities associated with socioeconomic status (SES). In a sample of youth with asthma, we investigated the potential buffering effects of maternal involvement and warmth on SES disparities in asthma-related immune responses, assessed via glucocorticoid resistance (GR) of immune cells. METHODS: One hundred and forty-three youth (10-16 years of age) with asthma completed measures of maternal involvement and warmth, and their primary caregivers reported their levels of education, income, and financial stress. Peripheral blood mononuclear cells from youth's blood were isolated, cultured, and assayed to determine mitogen-stimulated (PMA/INO + Etho) and mitogen/hydrocortisone-stimulated (PMA/INO + Cort) levels of two Th-2 cytokines (i.e., interleukin-5, interleukin-13) and one Th-1 cytokine (i.e., interferon-γ). GR was calculated by subtracting log-transformed cytokine concentration in the PMA/INO + Etho samples from log-transformed cytokine concentration in the PMA/INO + Cort samples. RESULTS: Both maternal involvement and warmth moderated the indirect pathway from family SES to GR of Th-2 cytokines via financial stress. Specifically, we found that low family SES was associated with elevated GR of Th-2 cytokines via increased financial stress among youth reporting low levels of maternal involvement and warmth, but not among those reporting high levels of maternal involvement or warmth. CONCLUSIONS: These results highlight the protective role of maternal involvement and warmth in health-related biological processes modulated by family SES among youth with asthma.