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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)757-768
Number of pages12
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1859
Issue number5
DOIs
Publication statusPublished - May 1 2016

Fingerprint

Retroelements
Somatomedins
Exons
Interspersed Repetitive Sequences
Messenger RNA
Alternative Splicing

Keywords

  • Alternative splicing
  • IGF-1 isoforms
  • Intrinsically disordered regions
  • Retroposon exonization
  • Synonymous sites

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Genetics
  • Molecular Biology
  • Structural Biology

Cite this

MIR retroposon exonization promotes evolutionary variability and generates species-specific expression of IGF-1 splice variants. / Annibalini, Giosuè; Bielli, Pamela; De Santi, Mauro; Agostini, Deborah; Guescini, Michele; Sisti, Davide; Contarelli, Serena; Brandi, Giorgio; Villarini, Anna; Stocchi, Vilberto; Sette, Claudio; Barbieri, Elena.

In: Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, Vol. 1859, No. 5, 01.05.2016, p. 757-768.

Research output: Contribution to journalArticle

Annibalini, Giosuè ; Bielli, Pamela ; De Santi, Mauro ; Agostini, Deborah ; Guescini, Michele ; Sisti, Davide ; Contarelli, Serena ; Brandi, Giorgio ; Villarini, Anna ; Stocchi, Vilberto ; Sette, Claudio ; Barbieri, Elena. / MIR retroposon exonization promotes evolutionary variability and generates species-specific expression of IGF-1 splice variants. In: Biochimica et Biophysica Acta - Gene Regulatory Mechanisms. 2016 ; Vol. 1859, No. 5. pp. 757-768.
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AU - Annibalini, Giosuè

AU - Bielli, Pamela

AU - De Santi, Mauro

AU - Agostini, Deborah

AU - Guescini, Michele

AU - Sisti, Davide

AU - Contarelli, Serena

AU - Brandi, Giorgio

AU - Villarini, Anna

AU - Stocchi, Vilberto

AU - Sette, Claudio

AU - Barbieri, Elena

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