The nucleus is highly organized, such that factors involved in the transcription and processing of distinct classes of RNA are confined within specific nuclear bodies^1,2. One example is the nuclear speckle, which is defined by high concentrations of protein and noncoding RNA regulators of pre-mRNA splicing³. What functional role, if any, speckles might play in the process of mRNA splicing is unclear^4,5. Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs and higher co-transcriptional splicing levels than genes that are located farther from nuclear speckles. Gene organization around nuclear speckles is dynamic between cell types, and changes in speckle proximity lead to differences in splicing efficiency. Finally, directed recruitment of a pre-mRNA to nuclear speckles is sufficient to increase mRNA splicing levels. Together, our results integrate the long-standing observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a crucial role for dynamic three-dimensional spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing.

细胞核是高度组织化的，因此参与不同类别 RNA 的转录和加工的因子被限制在特定的核体内^1,2。一个例子是核斑点，它是由高浓度的蛋白质和前体 mRNA 剪接的非编码 RNA 调节因子定义的³。斑点在 mRNA 剪接过程中可能发挥什么功能作用（如果有的话）尚不清楚^4,5。在这里，我们发现，与远离核斑点的基因相比，位于核斑点附近的基因表现出更高的剪接体浓度、与其前体mRNA的剪接体结合增加以及更高的共转录剪接水平。核斑点周围的基因组织在细胞类型之间是动态的，斑点接近度的变化导致剪接效率的差异。最后，将前 mRNA 定向募集至核斑点足以提高 mRNA 剪接水平。总之，我们的结果将长期观察到的核斑点与 mRNA 剪接的生物化学结合起来，并证明了基因组 DNA 的动态三维空间组织在驱动剪接体浓度和控制 mRNA 剪接效率方面的关键作用。