Nuclear speckles enable processing of RNA from GC-rich isochores

Nuclear speckles are conserved, membrane-less organelles linked to various post-transcriptional processes. Here, we examined their roles in human cells by engineered, acute removal of SON and SRRM2, two conserved speckle core components characterized by intrinsically disordered regions (IDRs). Their removal results in a significant downregulation of GC-rich genes with short introns clustered within GC-rich isochores, caused by inefficient and chaotic splicing; in contrast, the expression or splicing of genes outside these isochores remains unaffected. Comparative analysis across eukaryotes, from fungi to mammals, reveals that both GC-rich isochores and speckles are found exclusively in amniotes; moreover, the IDRs of SON have undergone notable expansion in the latter. Together, these findings suggest that the expansion of IDRs in vertebrates facilitated an increase in GC content by creating a condensate essential for splicing the by-products of this process: GC-rich, leveled exon-intron architectures.