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, 170 (2), 324-339.e23

Regulatory Expansion in Mammals of Multivalent hnRNP Assemblies That Globally Control Alternative Splicing

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Regulatory Expansion in Mammals of Multivalent hnRNP Assemblies That Globally Control Alternative Splicing

Serge Gueroussov et al. Cell.

Abstract

Alternative splicing (AS) patterns have diverged rapidly during vertebrate evolution, yet the functions of most species- and lineage-specific splicing events are not known. We observe that mammalian-specific AS events are enriched in transcript sequences encoding intrinsically disordered regions (IDRs) of proteins, in particular those containing glycine/tyrosine repeats that mediate formation of higher-order protein assemblies implicated in gene regulation and human disease. These evolutionary changes impact nearly all members of the hnRNP A and D families of RNA binding proteins. Regulation of these events requires formation of unusual, long-range mammalian-specific RNA duplexes. Differential inclusion of the alternative exons controls the formation of tyrosine-dependent multivalent hnRNP assemblies that, in turn, function to globally regulate splicing. Together, our results demonstrate that AS control of IDR-mediated interactions between hnRNPs represents an important and recurring mechanism underlying splicing regulation. Furthermore, this mechanism has expanded the regulatory capacity of mammalian cells.

Keywords: alternative splicing; evolution; hnRNP; multivalent assemblies; phase separation; protein disorder.

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