Gene architecture directs splicing outcome in separate nuclear spatial regions

Area of Science:

• Molecular Biology
• Genomics
• Cell Biology

Background:

• The mechanism by which the splicing machinery distinguishes exons from introns has been a long-standing enigma in molecular biology.
• Gene architecture and nuclear organization are known to influence gene expression, but their direct link to splicing outcomes remains unclear.

Purpose of the Study:

• To investigate how distinct exon-intron GC content architectures of genes, based on their nuclear localization, affect splicing outcomes.
• To elucidate the role of nuclear compartmentalization in regulating alternative splicing through different gene architectures.

Main Methods:

• Analysis of gene localization within the nucleus (peripheral vs. central) based on exon-intron GC content.
• Examination of splicing outcomes, including exon skipping and intron retention, for genes in different nuclear compartments.
• Identification of distinct splicing factor subnetworks associated with different gene architectures and nuclear regions.

Main Results:

• Genes in the nuclear periphery exhibit low GC content exons and long introns, favoring exon definition and resulting in exon skipping.
• Genes in the nuclear center possess high GC content exons and short introns, promoting intron definition and leading to intron retention.
• Two distinct sets of splicing factors form separate regulatory networks, correlating with the two gene architectures and nuclear regions.

Conclusions:

• The nucleus is compartmentalized into distinct functional regions (periphery and center) that differentially regulate alternative splicing.
• Gene exon-intron GC content architecture dictates its localization and the predominant mode of splicing (exon vs. intron definition).
• This study establishes a direct link between 3D genome organization and splicing regulation, explaining differential splicing outcomes in distinct nuclear environments.