The parental conflict hypothesis is a widely accepted explanation for genomic imprinting. This hypothesis is based on the conflicting interests of the maternal and paternal genomes during the offspring’s growth and development. The paternal genes are directed towards the growth and fitness of the fetus, enhancing the chances of his genome to be passed on to successive generations. The maternal genome attempts to limit fetal growth in order to distribute equal resources to each member of her offspring, while ensuring her own health and survival during delivery to be able to reproduce again. In keeping with this hypothesis, paternally expressed genes are generally growth promoting for the fetus, whereas maternally expressed genes are growth restricting.
IGF2 is a paternally expressed imprinted gene. It is a protein that promotes growth and cellular differentiation during development, and in mammals, it also regulates the placental supply of nutrients and signals the demand of nutrients by the fetus. It is considered an important human fetal growth promoter that is regulated by an imprinting control region (ICR1) that is shared with the nearby H19 gene, which is also oppositely imprinted in humans. In the case of imprinted genes that are expressed during fetal life, including IGF2, their transcription is potentially more vulnerable to changes. Alterations in transcriptional regulation, through either mutations or disturbed epigenetic processes may lead to functional abnormalities and disease states. In mice deletion of IGF2 gene results in poor fetal growth, and deletion of the opposing H19 with resultant over-production of IGF2, results in fetal overgrowth. In humans, imprinting defects in the IGF2-H19 gene locus are linked to major fetal growth syndromes like Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome, which causes under- and over-growth, respectively.
The phenomenon of genomic imprinting is both interesting in a biological sense and also strongly influences how we assess metabolic processes in health and disease. In a new study published in Journal Development, University of Cambridge scientists, Dr. Bethany Aykroyd, Dr. Simon Tunster and Dr Amanda Sferruzzi-Perri explored the role of imprinting of IGF2-H19 in fetal growth and its role in placental endocrine function. They used a mouse model where the imprinting control region (ICR1) that controls the expression of IGF2 and H19 genes, was deleted. In this study, researchers deleted ICR1 in the placental Jz of the mice, which lead to increased IGF2 and reduced H19 expression in just this placental region. The authors noticed an increased expression of pregnancy-specific glycoprotein 23 in the fetus’s placenta of both sexes. It also caused changes in Jz volume, with 20% increased Jz volume in males and 43% in females. The variable effects on Jz size with ICR1 deletion were linked to sex-specific changes in signalling pathways in the placenta of the fetuses. The research group found that deletion of ICR1 did not cause any changes in fetal mass, but this was likely caused by a knock-on effect of the Jz ICR1 deletion to reduce placental glucose transportation. Thus, the study concluded the deletion of ICR1 resulted in the increased Jz hormone output, though there were differences in both the sexes. They also highlighted there can be side effects of placental endocrine alterations on other placenta functions.
These experimental studies sought to investigate the role of imprinted genes on placenta function and thus their influence on fetal and maternal health. Researchers are especially interested in the endocrine role of the placenta because it will help find ways to prevent pregnancy issues like gestational diabetes, restricted fetal growth, fetal overgrowth, and more. Such pregnancy complications can impact on both the immediate and life-long health of the mother and her child. Studies have identified that mothers or offspring exposed to a pregnancy complication are at higher risk of developing diseases, like type 2 diabetes in later life. Greater understanding of imprinted genes, may help us in the future to find interesting and novel targets for pharmaceutical intervention in pregnancy and metabolic diseases. Though the new study confirms the role of IGF2 and H19 expression and the role of maternal and paternal imprinted genes in resource allocation to fetus and placenta’s endocrinal activity, it also shows that there are perhaps other higher regulatory mechanisms, too.
Aykroyd, B. R. L., Tunster, S. J., & Sferruzzi-Perri, A. N. (2022). Loss of imprinting of the Igf2-H19 ICR1 enhances placental endocrine capacity via sex-specific alterations in signalling pathways in the mouse. Development (Cambridge, England), 149(1), dev199811.