Biology subjects

Seneviratne, S.

Publications and source records attributed to Seneviratne, S..

4 recordsLinked to original sources

bioRxiv2025

Selective alteration to CD4 T cell differentiation by heterozygous IRF4L116R protects against neuroinflammation

The decision of naive T cells to differentiate into a specific Th cell subset after antigen encounter is a critical pivot point of the immune response and, when out of balance, can lead to autoimmunity, allergy or immunodeficiency. Th subset differentiation is determined by the expression of transcription factors including IRF4. We here describe a point mutation (IRF4L116R) in the DNA-binding domain of IRF4 leading to a dysregulation of CD4-T cell subsets and their functions. This point mutation does not alter overall protein expression. In sharp contrast to IRF4-null mice, neither the CD4/CD8 ratio nor T cell activation and memory is altered in naive mice carrying the point mutation. However, IRF4L116R T cells are reduced in their capability to differentiate into Th1, Th17 and Treg cells in a dose-dependent manner, contrasting with the findings in IRF4KO T cells. Particularly striking is the loss of Th1-differentiation in T cells from homozygous Irf4L116R/L116R mice while T cells completely lacking IRF4 show no reduction in Th1 differentiation. Furthermore, despite maintained ability to generate Th17 cells, expression of the IRF4L116R variant protects mice against disease development in the Th17 cell-dependent EAE mouse model of neuroinflammation. This contrasts with IRF4 knock-out mice, where expression of one wild-type allele of IRF4 is sufficient for full disease development. Together our results show that the L116R point mutation in IRF4 can selectively alter the differentiation and function of some CD4 T cell subsets and suggest that the L116R mutation is not a classical loss- or gain-of-function variant.

immunology↗

bioRxiv2024

Evolution, diversity, function, and marker-based elimination of the disease susceptibility gene Snn1 in wheat

Septoria nodorum blotch (SNB), caused by Parastagonospora nodorum, is a disease of durum and common wheat initiated by the recognition of pathogen-produced necrotrophic effectors (NEs) by specific wheat genes. The wheat gene Snn1 encodes a wall-associated kinase that directly interacts with the NE SnTox1 leading to the development of SNB. Here, sequence analysis of Snn1 from 114 accessions including diploid, tetraploid and hexaploid wheat species revealed that some wheat lines possess two copies of Snn1 (designated Snn1-B1 and Snn1-B2) approximately 120 kb apart. Snn1-B2 evolved relatively recently as a paralog of Snn1-B1, and both genes have undergone diversifying selection. Three point mutations associated with the formation of the first SnTox1-sensitive Snn1-B1 allele from a primitive wild wheat were identified. Four subsequent and independent SNPs, three in Snn1-B1 and one in Snn1-B2, converted the sensitive alleles to insensitive forms. Protein modeling indicated these four mutations could abolish Snn1-SnTox1 compatibility either through destabilization of the Snn1 protein or direct disruption of the protein-protein interaction. High-throughput markers were developed for the causal mutations and evaluated on panels of durum and common wheat. The markers were able to correctly identify 96.9 % of SnTox1-sensitive durum wheat accessions, and a marker for the null allele was 100% accurate at predicting SnTox1-insensitive lines in both durum and spring wheat. Results of this study increase our understanding of the evolution, diversity, and function of Snn1-B1 and Snn1-B2 genes and will be useful for marker-assisted elimination of these genes for better host resistance.

genetics↗

bioRxiv2021

A triple threat: the Parastagonospora nodorum SnTox267 effector exploits three distinct host genetic factors to cause disease in wheat

Parastagonospora nodorum is a fungal pathogen of wheat. As a necrotrophic specialist, it deploys a suite of effector proteins that target dominant host susceptibility genes to elicit programmed cell death (PCD). Nine effector - host susceptibility gene interactions have been reported in this pathosystem, presumed to be governed by unique pathogen effectors. This study presents the characterization of the SnTox267 necrotrophic effector that hijacks two separate host pathways to cause necrosis. An association mapping approach identified SnTox267 and the generation of gene-disrupted mutants and gain-of-function transformants confirmed its role in Snn2-, Snn6-, and Snn7-mediated necrosis. The Snn2 and Snn6 host susceptibility genes were complementary, and together they functioned cooperatively to elicit SnTox267-induced necrosis in the same light-dependent PCD pathway. Additionally, we showed that SnTox267 targeted Snn7, resulting in light-independent necrosis. Therefore, SnTox267 co-opts two distinct host pathways to elicit PCD. SnTox267 sequence comparison among a natural population of 197 North American P. nodorum isolates revealed 20 protein isoforms conferring variable levels of virulence, indicating continuing selection pressure on this gene. Protein isoform prevalence among discrete populations indicated that SnTox267 has likely evolved in response to local selection pressures and has diversified more rapidly in the Upper Midwest. Deletion of SnTox267 resulted in the upregulation of the unrelated effector genes SnToxA, SnTox1, and SnTox3, providing evidence for a complex genetic compensation mechanism. These results illustrate a novel evolutionary path by which a necrotrophic fungal pathogen uses a single proteinaceous effector to hijack two host pathways to induce cell death.

pathology↗

bioRxiv2020

Functional in vivo characterization of zebrafish sox10 enhancers in melanoma and neural crest

The re-emergence of a neural crest transcriptional program, including Sox10 upregulation, is a key step in melanoma initiation in humans and zebrafish. We hypothesize that epigenetic regulation of sox10 modulates melanoma initiation. ATAC-Seq analysis of zebrafish melanoma tumors identifies recurrently open chromatin domains near sox10. Reporter constructs for each putative sox10 enhancer were examined in zebrafish embryos for neural crest activity and in stable transgenic lines for melanoma activity. One element, peak5 (23 kilobases upstream of sox10), drives EGFP reporter expression in a subset of neural crest cells, Kolmer-Agduhr neurons, and early melanoma patches and tumors with high specificity. A [~]200 bp region, conserved across the Cyprinidae family (fish), is required for peak5 activity in neural crest and melanoma, and contains dimeric SoxE binding sites essential for neural crest activity. Our work identifies a novel melanoma transcriptional enhancer, expanding our knowledge of epigenetic regulation of neural crest identity in melanoma.

cancer biology↗