Dynamics of RNA localization to nuclear speckles are connected to splicing efficiency

Abstract

Nuclear speckles, a type of membraneless nuclear organelle in higher eukaryotic cells, play a vital role in gene expression regulation. Using the reverse transcription-based RNA-binding protein binding sites sequencing (ARTR-seq) method, we study human transcripts associated with nuclear speckles. We identify three gene groups whose transcripts demonstrate different speckle localization properties and dynamics: stably enriched in nuclear speckles, transiently enriched in speckles at the pre-mRNA stage, and not enriched in speckles. Specifically, we find that stably-enriched transcripts contain inefficiently spliced introns. We show that nuclear speckles specifically facilitate splicing of speckle-enriched transcripts. We further reveal RNA sequence features contributing to transcript speckle localization, underscoring a tight interplay between genome organization, RNA cis-elements, and transcript speckle enrichment, and connecting transcript speckle localization with splicing efficiency. Finally, we show that speckles can act as hubs for the regulated retention of introns during cellular stress. Collectively, our data highlight a role of nuclear speckles in both co- and post-transcriptional splicing regulation.

Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

“…Surprisingly, we show that transcript-centric IR levels are positively associated with nuclear speckle proximity, such that speckle-associated features exhibit significantly higher intron retention signatures, in contrast to those that are speckle distant ( Figure 4h ). Although conceptually these results run counter to patterns of higher splicing efficiency reported at nuclear speckles, they are otherwise consistent with evidence that specific, inefficiently spliced mRNA subpopulations are stably enriched in nuclear speckles 31,36,37 .…”

Senescent cells cluster CTCF on nuclear speckles to sustain their splicing program

“…However, senescent cells need to execute a radically different gene expression program and do this in the context of reduced overall transcriptional potency. In homeostasis, nuclear speckles can induce splicing and accelerate the processing of RNAs located in their vicinity, while also buffering the availability of its components between the different nuclear compartments 33,84 . Here, we show that disruption of SICCs via SRRM2 or BANF1 depletion leads to the near-complete reversal of splicing patterns induced upon senescence entry.…”