Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
Clin Immunol. 2024 Jul;264:110261. doi: 10.1016/j.clim.2024.110261. Epub 2024 May 22.
Gene regulatory elements, such as enhancers, greatly influence cell identity by tuning the transcriptional activity of specific cell types. Dynamics of enhancer landscape during early human Th17 cell differentiation remains incompletely understood. Leveraging ATAC-seq-based profiling of chromatin accessibility and comprehensive analysis of key histone marks, we identified a repertoire of enhancers that potentially exert control over the fate specification of Th17 cells. We found 23 SNPs associated with autoimmune diseases within Th17-enhancers that precisely overlapped with the binding sites of transcription factors actively engaged in T-cell functions. Among the Th17-specific enhancers, we identified an enhancer in the intron of RORA and demonstrated that this enhancer positively regulates RORA transcription. Moreover, CRISPR-Cas9-mediated deletion of a transcription factor binding site-rich region within the identified RORA enhancer confirmed its role in regulating RORA transcription. These findings provide insights into the potential mechanism by which the RORA enhancer orchestrates Th17 differentiation.
基因调控元件，如增强子，通过调节特定细胞类型的转录活性，极大地影响细胞特性。早期人类 Th17 细胞分化过程中增强子景观的动态变化仍不完全清楚。利用基于 ATAC-seq 的染色质可及性分析和关键组蛋白标记的综合分析，我们确定了一套潜在控制 Th17 细胞命运特化的增强子。我们在 Th17 增强子中发现了 23 个与自身免疫性疾病相关的单核苷酸多态性，这些 SNP 与积极参与 T 细胞功能的转录因子的结合位点精确重叠。在 Th17 特异性增强子中，我们鉴定到一个位于 RORA 内含子中的增强子，并证实该增强子正向调节 RORA 的转录。此外，CRISPR-Cas9 介导的缺失鉴定到的 RORA 增强子中富含转录因子结合位点的区域，证实了该区域在调节 RORA 转录中的作用。这些发现为 RORA 增强子调控 Th17 分化的潜在机制提供了线索。
