Abstract
The secreted protein, insulin-like growth factor 2 (IGF2), plays a central role in fetal and prenatal growth and development, and is regulated at the genetic level by parental imprinting, being expressed predominantly from the paternally derived chromosome in mice and humans. Here, IGF2/Igf2 and its locus has been examined in 19 mammals from 13 orders spanning ~166 million years of evolutionary development. By using human or mouse DNA segments as queries in genome analyses, and by assessing gene expression using RNA-sequencing libraries, more complexity was identified within IGF2/Igf2 than was annotated previously. Multiple potential 5’ non-coding exons were mapped in most mammals and are presumably linked to distinct IGF2/Igf2 promoters, as shown for several species by interrogating RNA-sequencing libraries. DNA similarity was highest in IGF2/Igf2 coding exons; yet, even though the mature IGF2 protein was conserved, versions of 67 or 70 residues are produced secondary to species-specific maintenance of alternative RNA splicing at a variable intron-exon junction. Adjacent H19 was more divergent than IGF2/Igf2, as expected in a gene for a noncoding RNA, and was identified in only 10/19 species. These results show that common features, including those defining IGF2/Igf2 coding and several non-coding exons, were likely present at the onset of the mammalian radiation, but that others, such as a putative imprinting control region 5’ to H19 and potential enhancer elements 3’ to H19, diversified with speciation. This study also demonstrates that careful analysis of genomic and gene expression repositories can provide new insights into gene structure and regulation.
Highlights
Insulin-like growth factor 2 (IGF2), a 67-amino acid single-chain secreted protein, plays a central role in human fetal growth and development, and is involved in a variety of physiological and patho-physiological processes in other mammalian species [1,2,3,4,5,6]
Mammalian Igf2 - H19 locus and genes observed in Beckwith-Wiedemann syndrome [7, 8], and its diminished expression appears to cause the reduced growth and bodily dysmorphism seen in Silver-Russell syndrome [7, 8]
In paternal chromatin imprinting control region (ICR) DNA becomes methylated on cytosine residues in CpG dinucleotides, which interferes with CCTC binding factor (CTCF) binding, and allows the enhancers to activate IGF2/Igf2 [16, 17, 19]
Summary
Insulin-like growth factor 2 (IGF2), a 67-amino acid single-chain secreted protein, plays a central role in human fetal growth and development, and is involved in a variety of physiological and patho-physiological processes in other mammalian species [1,2,3,4,5,6]. The locus includes tyrosine hydroxylase (TH/Th), INS (Ins in mice), H19, and other genes In both species, parental imprinting reciprocally regulates expression of IGF2/Igf and H19 genes in most cells and tissues [13, 14]. An imprinting control region (ICR) mediates this chromosome-of origin-specific gene expression via DNA sequences that encode recognition sites for the protein, CCTC binding factor (CTCF) [15,16,17,18]. In paternal chromatin ICR DNA becomes methylated on cytosine residues in CpG dinucleotides, which interferes with CTCF binding, and allows the enhancers to activate IGF2/Igf2 [16, 17, 19]
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