Cross-species clues of an epigenetic imprinting regulatory code for the <i>IGF2R </i>gene

The epigenetic marks on the <i>IGF2R </i>gene that encodes a receptor responsible for IGF-II degradation consist of differentially methylated DNA in association with multiple modifications on the associated histones. We review these epigenetic marks across various species during the evolution of <i>IGF2R </i>imprinting. Both<i> IGF2</i> and<i> IGF2R </i>genesare imprinted in the mammal lineage that diverged from Monotremata approximately 150 million years ago. While <i>IGF2 </i>is consistently imprinted in all mammals following its divergence, <i>IGF2R </i>imprinting disappears in the Euarchonta lineage, including human species, approximately 75 million years ago. Differential DNA methylation marks on the two parental alleles correlate with imprinting in all imprinted genes including <i>IGF2R</i>. While the DNA methylation marks in the <i>IGF2R </i>promoter region 1 (DMR1) correlate with <i>IGF2R </i>allelic expression, the DNA methylation marks in the intron region 2 (DMR2) fail to correlate with <i>IGF2R </i>imprinting status in a number of species. Human <i>IGF2R</i> and mouse neuronal <i>Igf2r</i> are not imprinted despite the presence of DMR2. We have noted that human <i>IGF2R </i>is not imprinted in more than 100 informative samples including various tumor tissues. Furthermore, opossum (Marsupialia) <i>IGF2R </i>is consistently imprinted despite the absence of DMR2. These lines of evidence indicate that DNA methylation marks in DMR2 are neither necessary nor sufficient for consistent imprinting of <i>IGF2R</i> across species. Histone modification marks, however, correlate more consistently with the tissue-specific and species-specific imprinting status of <i>IGF2R </i>in human and mouse. Acetylated histone H3 and H4 and methylated lysine 4 of H3 (H3-K4Me) associate with transcriptionally active alleles while tri-methylated lysine 9 of H3 (H3-K9Me3) marks the silenced alleles. In the mouse, an antisense non-coding transcript called <i>Air </i>is transcribed from DMR2 on the paternal allele, and this imprinted transcript plays a central role in <i>Igf2r </i>imprinting. Mouse <i>Igf2r </i>imprinting depends on an <i>Air </i>RNA while the existence of <i>AIR </i>in other species is unknown. Overall, DNA methylation, histone acetylation, and histone methylation play a vital role in coordinating <i>IGF2R </i>allelic expression across all species. Rare monoallelic or skewed allelic expression of human <i>IGF2R</i> and their biological importance warrants further rigorous study.