Systematic mapping of nuclear domain-associated transcripts reveals speckles and lamina as hubs of functionally distinct retained introns

Raw files for microscopy and western blot data presented in this study. *AR. Barutcu and M. Wu equally contributed to this study. SUMMARY The nucleus is highly compartmentalized through the formation of distinct classes of membraneless domains, yet the composition and function of many of these structures is not well understood. Using APEX2-mediated proximity labelling and RNA sequencing, we surveyed transcripts associated with nuclear speckles, several additional domains, and the lamina. Remarkably, speckles and lamina are associated with distinct classes of retained introns enriched in genes that function in RNA processing, translation, and the cell cycle. In contrast to the lamina-proximal introns, retained introns associated with speckles are relatively short, GC-rich, and enriched for functional sites of RNA binding proteins that are concentrated in these domains. They are also highly differentially regulated across diverse cellular contexts, including the cell cycle. Our study thus provides a resource of nuclear domain-associated transcripts and further reveals speckles and lamina as hubs of distinct populations of retained introns linked to gene regulation and cell cycle progression.本研究中显微镜成像与蛋白质印迹（western blot）数据的原始文件。 *AR·巴吕特库（AR. Barutcu）与M·吴（M. Wu）对本研究贡献均等。 研究概述 细胞核通过形成多种不同类别的无膜结构域实现高度区域化，但目前对多数此类结构的组成与功能仍知之甚少。本研究借助APEX2介导的邻近标记技术与RNA测序，对与核斑（nuclear speckles）、其他若干结构域以及核纤层（lamina）相关的转录本开展了系统性普查。值得注意的是，核斑与核纤层分别与不同类别的滞留内含子相关，这类内含子富集于参与RNA加工、翻译及细胞周期调控的基因中。与核纤层邻近的滞留内含子不同，与核斑相关的滞留内含子通常长度较短、GC含量更高，且富集于集中于此类结构域的RNA结合蛋白的功能结合位点。此外，这类滞留内含子在包括细胞周期在内的多种细胞环境中呈现显著的差异调控特征。本研究不仅为核结构域相关转录本提供了一份研究资源，还进一步揭示核斑与核纤层分别作为不同群体滞留内含子的枢纽，这些内含子与基因调控及细胞周期进程紧密关联。