Functional Polymorphism in the Parental Imprinting of the Human IGF2R Gene

doi:10.1006/bbrc.1993.2542

Biochemical and Biophysical Research Communications

Volume 197, Issue 2, 15 December 1993, Pages 747-754

https://doi.org/10.1006/bbrc.1993.2542 Get rights and content

Abstract

The murine genes coding for insulin-like growth factor II (Igf2) and its specific receptor (Igf2r) are parentally imprinted, with exclusive expression from the paternal (Igf2) or maternal (Igf2r) gene copy. We have demonstrated that the human IGF2 gene is imprinted, like its murine homologue. To examine whether the human IGF2R is also imprinted, we used CA repeat polymorphisms of the cDNA sequence to distinguish expression from each copy. Unlike the mouse, most subjects equally expressed both gene copies. However, two out of 14 informative fetuses showed exclusive expression from the maternal gene copy. We conclude that the human IGF2R gene is parentally imprinted, like its murine homologue, but only in a minority of individuals. This is the first direct demonstration of imprinting as a polymorphic trait, a property that had been observed in transgene methylation and predicted from the behavior of certain human tumors.

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Cited by (204)

Genomic imprinting of the IGF2R/AIR locus is conserved between bovines and mice
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Citation Excerpt :
It is transcribed from the maternal allele in all adult mouse tissues except for the brain, where it is expressed from both parental alleles [18,19]. In humans, IGF2R was initially reported to be not imprinted [20]; however, polymorphic paternal imprinting was found in early placental and fetal tissue samples [16,21,22]. Previous research has reported the tissue-specific imprinting status of bovine IGF2R in first trimester conception (Day 80 post fertilization).
Genomic imprinting is an epigenetic phenomenon that leads to genes monoallelically expressed in a parent-of-origin-specific manner and plays an important role in the embryonic development and postnatal growth of mammals. Imprinted genes usually occur in clusters in a chromosomal region and are regulated by a cis-acting imprinting control region that involves differential DNA methylation modification. Igf2r, Slc22a2 and Slc22a3 are three maternally expressed genes on mouse chromosome 17. The paternally expressed long noncoding RNA (lncRNA) Air and the nonimprinted gene Slc22a1 are also located in the imprinted region. Comparative characterization of imprinted clusters between species is useful for us to understand the biological significance and epigenetic regulating mechanism of genomic imprinting. The aim of this study was to analyze the allelic expression pattern of AIR and SLC22A1-3 genes in cattle and to determine the role of DNA methylation in regulating gene expression. Allelic expression analysis was performed in bovine adult tissues and term placenta using an SNP-based approach. We found that IGF2R, AIR and SLC22A3 were monoallelically expressed in all detected bovine somatic tissues, including heart, liver, spleen, lung, kidney, muscle, fat and brain. In bovine placenta, IGF2R and SLC22A3 are maternally expressed; however, the AIR gene is paternally expressed. Tissue-specific monoallelic expression of SLC22A2 is detected in bovines, with monoallelic expression in the spleen and brain but biallelic expression in kidney tissues. SLC22A1 is only detected in bovine liver and kidney tissues and is biallelicly expressed, which is consistent with the imprint expression in mice. To determine the possible role of DNA methylation in regulating the monoallelic/imprinted expression of bovine IGF2R, AIR, SLC22A2, and SLC22A3 genes, we analyzed the DNA methylation status of CpG islands in the first exon of SLC22A2, the promoter region of SLC22A3 and region 2 in the second intron of the IGF2R gene by bisulfite sequencing. Two differentially methylated regions (DMRs) were detected in the first exon of bovine SLC22A3 and the common regions of IGF2R and AIR. This suggests that DNA methylation is involved in the regulation of monoallelic/imprinted expression of IGF2R, AIR and SLC22A3 genes in cattle.
ImprintSeq, a novel tool to interrogate DNA methylation at human imprinted regions and diagnose multilocus imprinting disturbance
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Disruptions of genomic imprinting are associated with congenital imprinting disorders (CIDs) and other disease states, including cancer. CIDs are most often associated with altered methylation at imprinted differentially methylated regions (iDMRs). In some cases, multiple iDMRs are affected causing multilocus imprinting disturbances (MLIDs). The availability of accurate, quantitative, and scalable high-throughput methods to interrogate multiple iDMRs simultaneously would enhance clinical diagnostics and research.
We report the development of a custom targeted methylation sequencing panel that covered most relevant 63 iDMRs for CIDs and the detection of MLIDs. We tested it in 70 healthy controls and 147 individuals with CIDs. We distinguished loss and gain of methylation per differentially methylated region and classified high and moderate methylation alterations.
Across a range of CIDs with a variety of molecular mechanisms, ImprintSeq performed at 98.4% sensitivity, 99.9% specificity, and 99.9% accuracy (when compared with previous diagnostic testing). ImprintSeq was highly sensitive for detecting MLIDs and enabled diagnostic criteria for MLID to be proposed. In a child with extreme MLID profile a probable genetic cause was identified.
ImprintSeq provides a novel assay for clinical diagnostic and research studies of CIDs, MLIDs, and the role of disordered imprinting in human disease states.
The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth
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In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here, we demonstrate, through fetal, endothelial, hematopoietic, and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The angiocrine effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signaling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.
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2020, Epigenetics and Reproductive Health
Placental development is of the greatest importance for fetal development and growth. The placenta has characteristic epigenetic features required for its proper development. Emerging studies have linked these features as mediators of environmental influence on diseases of gestation, pregnancy outcome and risk for diseases of later life. In addition to the understanding of biology and pathology of placental development, analyzing epigenetic alterations in the placenta will provide opportunities for the search of the biomarker for disease risk, its diagnosis, prognosis, treatment options, and preventive strategies. The chapter covers the process of placental development, the role of various epigenetic mechanisms i.e., DNA methylation, histone modification, non-coding RNAs therein. Disturbed placental epigenetics during various placental pathologies and maternal lifestyle and metabolic conditions are also discussed. Further extensive studies are required for using the biomarkers in clinical practice.
Soluble M6P/IGFIIR in the circulation
2015, Best Practice and Research: Clinical Endocrinology and Metabolism
Citation Excerpt :
Studies on regulation of M6P/IGFIIR demonstrated developmental regulation in many species with high abundance during fetal life and lower expression levels after birth [12,13]. Furthermore, in many species the M6P/IGFIIR gene was found to be regulated by imprinting with maternal repression of the paternal allele (see [14] for review), however in the human imprinting has been shown to be polymorphic [15] and the role of imprinting of the M6P/IGFIIR gene in the human still needs to be fully elucidated. The membrane M6P/IGFIIR is a 270–300 kDa glycoprotein comprised of a single polypeptide chain consisting of an extracytoplasmic domain of 15 cysteine rich, partly homologous repeats, a single transmembrane domain and a short cytoplasmic domain (Fig. 1).
Soluble M6P/IGFIIR has the potential to be a significant carrier of IGF-II and mannose 6-P proteins in the circulation and play an important role as an antagonist to the cellular receptor. Evidence suggests that soluble receptor plays a role in fetal and childhood growth by opposing the growth stimulatory effects of IGF-II. Maternal serum levels of M6P/IGFIIR are elevated in late pregnancy and the IGF-II:soluble M6P/IGFIIR ratio in cord blood correlates strongly with weight at birth and placental weight suggesting an important role in fetal growth and development. However, elevated soluble receptor levels may also be indicative of disease in later life, such as liver cirrhosis and some tumor types and may be a useful marker for monitoring treatment and progression of the disease. Further investigation of the regulation of this soluble receptor in health and disease is required to fully elucidate its role in the circulation.
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Regular ArticleFunctional Polymorphism in the Parental Imprinting of the Human IGF2R Gene

Abstract

Regular Article
Functional Polymorphism in the Parental Imprinting of the Human IGF2R Gene