Biology subjects

Kalita, C.

Publications and source records attributed to Kalita, C..

4 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↗

bioRxiv2022

Characterization of caffeine response regulatory variants in vascular endothelial cells

Genetic variants in gene regulatory sequences can modify gene expression and mediate the molecular response to environmental stimuli. In addition, genotype-environment interactions (GxE) contribute to complex traits such as cardiovascular disease. Caffeine is the most widely consumed stimulant and is known to produce a vascular response. To investigate GxE for caffeine, we treated vascular endothelial cells with caffeine and used a massively parallel reporter assay to measure allelic effects on gene regulation for over 43,000 genetic variants. We identified 665 variants with allelic effects on gene regulation and 29 variants that regulate the gene expression response to caffeine (GxE, FDR<10%). When overlapping our GxE results with eQTLs colocalized with CAD and hypertension, we dissected their regulatory mechanisms and showed a modulatory role for caffeine. Our results demonstrate that massively parallel reporter assay is a powerful approach to identify and molecularly characterize GxE in the specific context of caffeine consumption.

genomics↗

bioRxiv2021

Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

genetics↗

bioRxiv2021

A signature of Neanderthal introgression on molecular mechanisms of environmental responses

Ancient human migrations led to the settlement of population groups in varied environmental contexts worldwide. The extent to which adaptation to local environments has shaped human genetic diversity is a longstanding question in human evolution. Recent studies have suggested that introgression of archaic alleles in the genome of modern humans may have contributed to adaptation to environmental pressures such as pathogen exposure. Functional genomic studies have demonstrated that variation in gene expression across individuals and in response to environmental perturbations is a main mechanism underlying complex trait variation. We considered gene expression response to in vitro treatments as a molecular phenotype to identify genes and regulatory variants that may have played an important role in adaptations to local environments. We investigated if Neanderthal introgression in the human genome may contribute to the transcriptional response to environmental perturbations. To this end we used eQTLs for genes differentially expressed in a panel of 52 cellular environments, resulting from 5 cell types and 26 treatments, including hormones, vitamins, drugs, and environmental contaminants. We found that SNPs with introgressed Neanderthal alleles (N-SNPs) disrupt binding of transcription factors important for environmental responses, including ionizing radiation and hypoxia, and for glucose metabolism. We identified an enrichment for N-SNPs among eQTLs for genes differentially expressed in response to 8 treatments, including glucocorticoids, caffeine, and vitamin D. Using Massively Parallel Reporter Assays (MPRA) data, we validated the regulatory function of 21 introgressed Neanderthal variants in the human genome, corresponding to 8 eQTLs regulating 15 genes that respond to environmental perturbations. These findings expand the set of environments where archaic introgression may have contributed to adaptations to local environments in modern humans and provide experimental validation for the regulatory function of introgressed variants.

evolutionary biology↗