Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32601, USA.
University of Florida Genetics Institute, University of Florida, Gainesville, FL, 32601, USA.
Commun Biol. 2023 Sep 27;6(1):988. doi: 10.1038/s42003-023-05327-7.
Genome-wide association studies have identified numerous loci with allelic associations to Type 1 Diabetes (T1D) risk. Most disease-associated variants are enriched in regulatory sequences active in lymphoid cell types, suggesting that lymphocyte gene expression is altered in T1D. Here we assay gene expression between T1D cases and healthy controls in two autoimmunity-relevant lymphocyte cell types, memory CD4/CD25 regulatory T cells (Treg) and memory CD4/CD25 T cells, using a splicing event-based approach to characterize tissue-specific transcriptomes. Limited differences in isoform usage between T1D cases and controls are observed in memory CD4/CD25 T-cells. In Tregs, 402 genes demonstrate differences in isoform usage between cases and controls, particularly RNA recognition and splicing factor genes. Many of these genes are regulated by the variable inclusion of exons that can trigger nonsense mediated decay. Our results suggest that dysregulation of gene expression, through shifts in alternative splicing in Tregs, contributes to T1D pathophysiology.
全基因组关联研究已经确定了许多与 1 型糖尿病（T1D）风险相关的基因座。大多数与疾病相关的变异体富集在淋巴样细胞类型中活跃的调节序列中，这表明 T1D 中淋巴细胞基因表达发生改变。在这里，我们使用基于剪接事件的方法来描述组织特异性转录组，在两种与自身免疫相关的淋巴细胞细胞类型（记忆 CD4/CD25 调节性 T 细胞[Treg]和记忆 CD4/CD25 T 细胞）中检测 T1D 病例和健康对照之间的基因表达。在记忆 CD4/CD25 T 细胞中，T1D 病例和对照组之间的异构体使用差异有限。在 Tregs 中，402 个基因在病例和对照组之间的异构体使用上存在差异，特别是 RNA 识别和剪接因子基因。这些基因中的许多都受到可变外显子的调控，这些外显子可以触发无意义介导的衰变。我们的结果表明，Tregs 中通过可变剪接的失调导致基因表达的失调，这可能导致 T1D 的病理生理学发生变化。
