Biology subjects

Soskic, B.

Publications and source records attributed to Soskic, B..

9 recordsLinked to original sources

bioRxiv2026

Insulin synthesis is sustained by Tent5 poly(A) polymerases

Insulin is an essential regulator of glucose homeostasis in vertebrates, and impairment of its synthesis or action leads to diabetes with severe health complications in humans. It is therefore essential to understand how beta cells control insulin synthesis and secretion, including the transcription, translation and decay of its messenger RNA. Using sequencing-based poly(A) tail length profiling from human tissue, genetic evidence for type 2 diabetes, bulk and single-cell transcriptomics and perturbation experiments, here we find that the insulin mRNA is stabilized by the activity of noncanonical poly(A) polymerases of the Tent5 family. We show that Tent5 activity is specific, promoted by both localization at the endoplasmic reticulum and regulatory sequences within the insulin mRNA and regulated by glucose. Overall, our findings provide a mechanistic link between the dynamic control of insulin production by beta cells and the direct regulation of insulin mRNA metabolism.

molecular biology↗

bioRxiv2026

Division state reveals hidden genetic regulation during T cell activation and identifies immune disease-linked gene programmes

A major challenge in human genetics is to connect disease-associated variants to the cellular functions they perturb. Variants associated with immune-mediated disease have implicated CD4 T-cell activation as a disease-causal process; however, it remains unresolved whether these variants act on pathways initiating cell division, driving effector differentiation, or maintaining proliferative capacity. Activated T cells comprise mixtures of cells that have undergone different numbers of divisions, potentially obscuring genetic effects that act at specific stages of this process. Here, we study CD4 T-cell activation through cell division using division-resolved single-cell transcriptomics of naive, memory and regulatory T cells. We show that division state constitutes an important axis of transcriptional organisation, with approximately one third of genes exhibiting division-dependent regulation across shared and subset-specific programmes. We develop CellDivider, a machine-learning model that accurately infers proliferative state directly from single-cell transcriptomes, enabling a scalable approach for cohort level mapping of variant effects on cell proliferation phenotypes. Incorporating inferred division state into single-cell eQTL models reveals regulatory effects that are attenuated or missed when cells are analysed by activation time alone. Finally, we resolve gene expression programmes that govern distinct stages of T cell activation and proliferation. We show that polygenic immune disease risk preferentially converges on early activation and differentiation modules, rather than on proliferative capacity itself. Consistent with this model, division-resolved analysis of the pleiotropic immune risk gene RPS26 localises its genetic effects to early division states, providing mechanistic insight into its broad disease associations. Together, these findings illustrate how resolving dynamic cellular consequences of activation sharpens variant-to-function inference in immune disease genetics.

genetics↗

bioRxiv2025

Competing gene regulatory networks drive naive and memory B cell differentiation

Elucidating the gene regulatory networks (GRNs) that govern human B cell differentiation is essential for understanding immune responses to infection, vaccination and autoantigens. Here, we show that individual naive B cells can give rise to both plasma cells and germinal centre (GC) B cells. In contrast, memory B cells display a progressive increase in IRF4 activity over time, leading to PRDM1 induction and exclusive differentiation into plasma cells. Using CRISPR-based perturbations, we demonstrate that IRF4 is indispensable for both GC and plasma cell development. Notably, IRF4 promotes GC fate independently of PRDM1, as PRDM1 disruption did not impair GC differentiation. We also find that while the abundance of antibody mRNAs is clonally correlated, class switch recombination (CSR) occurs stochastically and is clonally independent. Together, these findings reveal distinct regulatory dynamics during naive and memory B cell activation and offer new insights into the GRNs underlying human B cell fate decisions.

immunology↗

bioRxiv2022

Cross-disorder genetic analysis of immune diseases reveals distinct disease groups and associated genes that converge on common pathogenic pathways

Genome-wide association studies (GWAS) have mapped thousands of susceptibility loci associated with immune-mediated diseases, many of which are shared across multiple diseases. To assess the extent of the genetic sharing across nine immune-mediated diseases we applied genomic structural equation modelling (genomic SEM) to GWAS data. By modelling the genetic covariance between these diseases, we identified three distinct groups: gastrointestinal tract diseases, rheumatic and systemic diseases, and allergic diseases. We identified 92, 103 and 91 genetic loci that predispose to each of these disease groups, with only 12 of them being shared across groups. Although loci associated with each of these disease groups were highly specific, they converged on perturbing the same pathways, primarily T cell activation and cytokine signalling. Finally, to assess whether variants associated with each disease group modulate gene expression in immune cells, we tested for colocalization between loci and single-cell eQTLs derived from peripheral blood mononuclear cells. We identified the causal route by which 47 loci contribute to predisposition to these three disease groups. In addition, given that the assessed variants are pleiotropic, we found evidence for eight of these genes being strong candidates for drug repurposing. Taken together, our data suggest that different constellations of diseases have distinct patterns of genetic association, but that associated loci converge on perturbing different nodes in a common set of T cell activation and signalling pathways.

genetics↗

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

Immune disease variants modulate gene expression in regulatory CD4+ T cells and inform drug targets

Identifying cellular functions dysregulated by disease associated variants could implicate novel pathways for drug targeting or modulation in cell therapies. Variants associated with immune diseases point towards the role of CD4+ regulatory T cells (Tregs), cell type critical for immune homeostasis. To translate the effects of immune disease alleles on Treg function we mapped genetic regulation (QTL) of gene expression and chromatin activity in Tregs. We identified 123 loci where Treg QTLs colocalized with immune disease variants. These colocalizations indicated that dysregulation of key Treg pathways, including cell activation via CD28 and IL-2 signalling mediated by STAT5A contribute to the shared pathobiology of immune diseases. Finally, using disease GWAS signals colocalizing with Treg QTLs, we identified 34 known drug targets and 270 targets with drug tractability evidence. Our study is the first in-depth characterization of immune disease variant effects on Treg gene expression modulation and dysregulation of Treg function.

genetics↗

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↗

bioRxiv2018

Genomic profiling of T cell activation reveals dependency of memory T cells on CD28 costimulation

T cell activation is a critical driver of immune response and if uncontrolled, it can result in failure to respond to infection or in excessive inflammation and autoimmunity. CD28 costimulatory pathway is an essential regulator of CD4 T cell responses. To deconvolute how T cell receptor (TCR) and CD28 orchestrate activation of human CD4 T cells we stimulated cells using varying intensities of TCR and CD28 signals followed by gene expression profiling. We demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Strikingly, cell cycle and cell division are sensitive to CD28 in memory cells, but under TCR control in naive cells, in contrast to the paradigm that memory cells are CD28-independent. Using a combination of chromatin accessibility and enhancer profiling, we observe that IRFs and Blimp-1 (PRDM1) motifs are enriched in naive and memory T cells in response to TCR. In contrast, memory cells initiate AP1 transcriptional regulation only when both TCR and CD28 are engaged, implicating CD28 as an amplifier of transcriptional programmes in memory cells. Lastly, we show that CD28-sensitive genes are enriched in autoimmune disease loci, pointing towards the role of memory cells and the regulation of T cell activation through CD28 in autoimmune disease development. This study provides important insights into the differential role of CD28 in naive and memory T cell responses and offers a new platform for design and interpretation of costimulatory based therapies.\n\nOne-sentence summaryGenomic profiling of CD4 T cell activation reveals a sensitivity switch from TCR in naive to CD28 in memory cells.

genomics↗