Nuclear speckles enable processing of RNA from GC-rich isochores

Area of Science:

• Cell Biology
• Genomics
• Molecular Biology

Background:

• Nuclear speckles are essential membrane-less organelles involved in post-transcriptional RNA processing.
• SON and SRRM2 are core components of nuclear speckles, featuring intrinsically disordered regions (IDRs).

Purpose of the Study:

• To investigate the function of nuclear speckles in human cells by analyzing the impact of SON and SRRM2 removal.
• To explore the evolutionary relationship between nuclear speckles, GC-rich isochores, and gene splicing in vertebrates.

Main Methods:

• Engineered acute removal of SON and SRRM2 proteins in human cells.
• Analysis of gene expression and splicing patterns, focusing on GC-rich gene clusters.
• Comparative genomic analysis across eukaryotes to identify the evolutionary emergence of speckles and GC-rich isochores.

Main Results:

• Removal of SON and SRRM2 led to significant downregulation of GC-rich genes with short introns within GC-rich isochores due to inefficient splicing.
• Genes outside GC-rich isochores were unaffected, indicating a specific role for speckles in splicing these sequences.
• Nuclear speckles and GC-rich isochores are exclusively found in amniotes, with notable expansion of SON's IDRs in vertebrates.

Conclusions:

• Nuclear speckles are critical for the efficient splicing of GC-rich genes, particularly in amniotes.
• The evolution of intrinsically disordered regions in SON likely facilitated the increase in GC content in vertebrate genomes.
• These findings reveal a co-evolutionary link between nuclear speckle function, IDR expansion, and the structural organization of the vertebrate genome.