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

Cell. 2017 Jul 13;170(2):324-339.e23. doi: 10.1016/j.cell.2017.06.037.


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.

MeSH terms

  • Alternative Splicing*
  • Amino Acid Sequence
  • Animals
  • Gene Expression Regulation
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism*
  • Humans
  • Mammals / genetics*
  • Mammals / metabolism
  • Protein Isoforms / metabolism
  • RNA Precursors / metabolism
  • Sequence Alignment
  • Vertebrates / genetics
  • Vertebrates / metabolism


  • Heterogeneous-Nuclear Ribonucleoproteins
  • Protein Isoforms
  • RNA Precursors