Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians

Abstract

Comparisons between eutherians and marsupials suggest limited conservation of the molecular mechanisms that control genomic imprinting in mammals. We have studied the evolution of the imprinted IGF2-H19 locus in therians. Although marsupial orthologs of protein-coding exons were easily identified, the use of evolutionarily conserved regions and low-stringency Bl2seq comparisons was required to delineate a candidate H19 noncoding RNA sequence. The therian H19 orthologs show miR-675 and exon structure conservation, suggesting functional selection on both features. Transcription start site sequences and poly(A) signals are also conserved. As in eutherians, marsupial H19 is maternally expressed and paternal methylation upstream of the gene originates in the male germline, encompasses a CTCF insulator, and spreads somatically into the H19 gene. The conservation in all therians of the mechanism controlling imprinting of the IGF2-H19 locus suggests a sequential model of imprinting evolution.

Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver–Russell syndrome phenotypes

“…Comparative genome studies have revealed extensive conservation of H19/Igf2 in therians (6). Consistently, key features of imprinting, as well as spatial organization of the mouse and human loci, are shared, including DNA methylation patterns, CTCF-binding sites (CTSs), and cis-regulatory elements.…”

The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1)

“…mechanism apart from imprinting regulation. 7,8 However, the detailed mechanism by which H19 performs its regulatory function via miR-675 on target genes has not been clarified.…”

Évolution de l’empreinte parentale chez les mammifères

“…Ceci suggère un déploiement spéci-fique des ICR chez les euthériens ou, alternativement, l'utilisation par les marsupiaux d'un mode de régulation indépendant de la méthylation. Le consortium SAVOIR (sequence analysis of vertebrate orthologous imprinted regions) a entrepris depuis plusieurs années l'analyse comparative systématique chez le poulet, le wallaby/kangourou et l'ornithorynque des régions orthologues des locus soumis à empreinte connus [21]. La publication récente de la séquence du génome de l'ornithorynque a facilité l'identification des régions synténiques et des éléments fonctionnels importants, en relation avec l'évolution des génomes [22].…”