Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Medical Scientist Training Program, Stony Brook University, Stony Brook, NY, USA.
Nat Commun. 2022 Aug 2;13(1):4296. doi: 10.1038/s41467-022-31750-1.
The induction of central T cell tolerance in the thymus depends on the presentation of peripheral self-epitopes by medullary thymic epithelial cells (mTECs). This promiscuous gene expression (pGE) drives mTEC transcriptomic diversity, with non-canonical transcript initiation, alternative splicing, and expression of endogenous retroelements (EREs) representing important but incompletely understood contributors. Here we map the expression of genome-wide transcripts in immature and mature human mTECs using high-throughput 5' cap and RNA sequencing. Both mTEC populations show high splicing entropy, potentially driven by the expression of peripheral splicing factors. During mTEC maturation, rates of global transcript mis-initiation increase and EREs enriched in long terminal repeat retrotransposons are up-regulated, the latter often found in proximity to differentially expressed genes. As a resource, we provide an interactive public interface for exploring mTEC transcriptomic diversity. Our findings therefore help construct a map of transcriptomic diversity in the healthy human thymus and may ultimately facilitate the identification of those epitopes which contribute to autoimmunity and immune recognition of tumor antigens.
胸腺中中央 T 细胞耐受的诱导取决于髓质胸腺上皮细胞（mTEC）对外周自身表位的呈递。这种混杂的基因表达（pGE）驱动 mTEC 转录组多样性，具有非规范的转录起始、可变剪接和内源性逆转录元件（EREs）的表达，这是重要但尚未完全理解的贡献因素。在这里，我们使用高通量 5' 帽和 RNA 测序来绘制未成熟和成熟人 mTEC 中全基因组转录物的表达图谱。两个 mTEC 群体都表现出高剪接熵，这可能是由外周剪接因子的表达驱动的。在 mTEC 成熟过程中，全局转录物错误起始的速率增加，富含长末端重复逆转录转座子的 EREs 上调，后者通常在差异表达基因附近发现。作为一种资源，我们提供了一个交互式公共界面，用于探索 mTEC 转录组多样性。因此，我们的发现有助于构建健康人类胸腺转录组多样性图谱，并最终有助于鉴定那些导致自身免疫和肿瘤抗原免疫识别的表位。
