The nucleus of mammalian cells is highly compartmentalized both in terms of DNA and protein organization. Speckles are large membrane-less irregularly shaped nuclear condensates with a dynamic composition of hundreds of different proteins, many of which are involved in RNA splicing. Evidence from recent studies points towards an interesting connection between the evolution of nuclear speckles and genome structure in terms of base composition, gene clustering and 3D-genome organization.

Nuclear speckles evolved in amniotes, concurrently with the emergence of genomes that contain long stretches with many short GC-rich genes, called H3 isochores. These genes, which tend to have short GC-rich introns flanking GC-rich exons, are prone to splicing errors in which intrones are retained and cryptic splice sites activated. Interestingly, the GC-rich H3 isochores have been shown to reside close to nuclear speckles (Chen, 2018), thus placing them close to a rich resource for splicing factors, likely in order to ensure proper splicing and thus gene expression.

Two proteins, SON and SRRM2, are essential for formation of nuclear speckles and seem to act as a major scaffolding core (Ilik, 2020). In a recent study published in Cell, Malszycki et al was able to show that simultaneous depletion of SON and SRRM2 resulted in complete dissolution of speckles. While this had little effect on global gene expression, it clearly disturbed both 3D-genome organization as well as gene expression in H3 isochores. In particular, loss of speckles resulted in disordered splicing, followed by impaired nuclear export and increased decay of mRNA from GC-rich genomic regions.

This supports a theory that nuclear speckles evolved to enable a genome structure with short GC-rich genes, in which exons are separated by short GC-rich introns, and that clustering of these within H3 isochores enables 3D-positioning close to nuclear speckles, ensuring access to high concentrations of splicing components, and reliable gene expression.