Biology subjects

Wille, D.

Publications and source records attributed to Wille, D..

4 recordsLinked to original sources

bioRxiv2025

Integrated QTL mapping and CRISPR screening in pooled iPSC-derived microglia reveals genetic drivers of neurodegenerative risk

Mounting evidence implicates microglia in neurodegeneration, but linking disease-associated genetic variants to target genes and cellular phenotypes is hindered by the inaccessibility of these cells. We differentiated 261 human iPSC lines into microglia-like cells (iMGL) in pools with phenotypic (differentiation, phagocytosis and migration) and single-cell transcriptomic readouts. Burden analysis of deleterious variants detected 36 genes influencing microglial phenotypes. Expression quantitative trait locus (eQTL) analysis found 7,121 eGenes, and 79 colocalizations across four neurodegenerative disease GWAS, half of which had limited prior evidence of causality. Integration of eQTL and phenotypic associations highlighted the role of disease-relevant variants including LRRK2 and TREM2 acting via microglial phagocytosis. A coupled CRISPR screen identified a role of TREM2 in phagocytosis and highlighted the importance of cellular state in directionality of phenotype. By contextualizing variant effects within disease-relevant microglial states, we provide a comprehensive framework for interpreting the function of risk loci in neurodegenerative disorders.

genomics↗

bioRxiv2021

Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation

During activation, T cells undergo extensive changes in gene expression which shape the properties of cells to exert their effector function. Therefore, understanding the genetic regulation of gene expression during T cell activation provides essential insights into how genetic variants influence the response to infections and immune diseases. We generated a single-cell map of expression quantitative trait loci (eQTL) across a T cell activation time-course. We profiled 655,349 CD4+ naive and memory T cells, capturing transcriptional states of unstimulated cells and three time points of cell activation in 119 healthy individuals. We identified 38 cell clusters, including stable clusters such as central and effector memory T cells and transient clusters that were only present at individual time points of activation, such as interferon-responding cells. We mapped eQTLs using a T cell activation trajectory and identified 6,407 eQTL genes, of which a third (2,265 genes) were dynamically regulated during T cell activation. We integrated this information with GWAS variants for immune-mediated diseases and observed 127 colocalizations, with significant enrichment in dynamic eQTLs. Immune disease loci colocalized with genes that are involved in the regulation of T cell activation, and genes with similar functions tended to be perturbed in the same direction by disease risk alleles. Our results emphasize the importance of mapping context-specific gene expression regulation, provide insights into the mechanisms of genetic susceptibility of immune diseases, and help prioritize new therapeutic targets.

genomics↗

bioRxiv2019

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Naive CD4+ T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. We used quantitative proteomics, bulk RNA-seq and single-cell RNA-seq of over 40,000 human naive and memory CD4+ T cells to generate a detailed map of cytokine-regulated gene expression programs. We demonstrated that cytokine response differs substantially between naive and memory T cells and showed that memory cells are unable to differentiate into the Th2 phenotype. Moreover, memory T cells acquire a Th17-like phenotype in response to iTreg polarization. At the single-cell level, we demonstrated that T cells form a continuum which progresses from naive to effector memory T cells. This continuum is accompanied by a gradual increase in the expression levels of chemokines and cytokines and thus represents an effectorness gradient. Finally, we found that T cell cytokine responses are determined by where the cells lie in the effectorness gradient and identified genes whose expression is controlled by cytokines in an effectorness-dependent manner. Our results shed light on the heterogeneity of T cells and their responses to cytokines, provide insight into immune disease inflammation and could inform drug development.

immunology↗

bioRxiv2019

Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases

Complex immune disease variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states or stages of cell activation is unknown. We stimulated T cells and macrophages in the presence of thirteen different cytokine cocktails linked to immune diseases and profiled active enhancers and promoters together with regions of open chromatin. We observed that T cell activation induced major chromatin remodelling, while additional exposure to cytokines fine-tuned the magnitude of these changes. Therefore, we developed a new statistical method that accounts for subtle changes in chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune disease variants in early rather than late activation of memory CD4+ T cells, and with limited differences across polarizing cytokines. Furthermore, we demonstrate that inflammatory bowel disease variants are enriched in chromatin regions active in Th1 cells, while asthma variants overlap regions active in Th2 cells. We also show that Alzheimers disease variants are enriched in different macrophage cell states. Our results represent the first in-depth analysis of immune disease variants across a comprehensive panel of activation states of T cells and macrophages.

genetics↗