MIR retroposon exonization promotes evolutionary variability and generates species-specific expression of IGF-1 splice variants

Claudio Sette, Giosuè Annibalini, Pamela Bielli, Mauro De Santi, Deborah Agostini, Michele Guescini, Davide Sisti, Serena Contarelli, Giorgio Brandi, Anna Villarini, Vilberto Stocchi, Elena Barbieri

Risultato della ricerca: Contributo in rivistaArticolo in rivista

16 Citazioni (Scopus)

Abstract

Insulin-like growth factor (IGF) -1 is a pleiotropic hormone exerting mitogenic and anti-apoptotic effects. Inclusion or exclusion of exon 5 into the IGF-1 mRNA gives rise to three transcripts, IGF-1Ea, IGF-1Eb and IGF-1Ec, which yield three different C-terminal extensions called Ea, Eb and Ec peptides. The biological significance of the IGF-1 splice variants and how the E-peptides affect the actions of mature IGF-1 are largely unknown. In this study we investigated the origin and conservation of the IGF-1 E-peptides and we compared the pattern of expression of the IGF-1 isoforms in vivo, in nine mammalian species, and in vitro using human and mouse IGF-1 minigenes. Our analysis showed that only IGF-1Ea is conserved among all vertebrates, whereas IGF-1Eb and IGF-1Ec are an evolutionary novelty originated from the exonization of a mammalian interspersed repetitive-b (MIR-b) element. Both IGF-1Eb and IGF-1Ec mRNAs were constitutively expressed in all mammalian species analyzed but their expression ratio varies greatly among species. Using IGF-1 minigenes we demonstrated that divergence in cis-acting regulatory elements between human and mouse conferred species-specific features to the exon 5 region. Finally, the protein-coding sequences of exon 5 showed low rate of synonymous mutations and contain disorder-promoting amino acids, suggesting a regulatory role for these domains. In conclusion, exonization of a MIR-b element in the IGF-1 gene determined gain of exon 5 during mammalian evolution. Alternative splicing of this novel exon added new regulatory elements at the mRNA and protein level potentially able to regulate the mature IGF-1 across tissues and species.
Lingua originaleEnglish
pagine (da-a)757-768
Numero di pagine12
RivistaBIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS
Volume1859
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Alternative Splicing
  • Alternative splicing
  • Animals
  • Biochemistry
  • Biophysics
  • Evolution, Molecular
  • Exons
  • Genetics
  • Humans
  • IGF-1 isoforms
  • Insulin-Like Growth Factor I
  • Intrinsically disordered regions
  • Mammals
  • Mice
  • Molecular Biology
  • Protein Isoforms
  • Retroelements
  • Retroposon exonization
  • Species Specificity
  • Structural Biology
  • Synonymous sites

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