Disease relevance of Igf2

• Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome [1].
• Soluble IGF2 receptor rescues Apc(Min/+) intestinal adenoma progression induced by Igf2 loss of imprinting [2].
• Increased expression of the normally monoallelic (paternally expressed) mouse (Igf2) and human (IGF2) genes modify progression of intestinal adenoma in the Apc(Min/+) mouse and correlate with a high relative risk of human colorectal cancer susceptibility, respectively [2].
• They also identify Igf2 as a potential target for medulloblastoma and RMS [3].
• The present study determined whether hyperhomocysteinemia produces decreased tissue methylation capacity, hypomethylation of the H19 DMD, and altered expression of H19 and Igf2 in adult mice [4].

Psychiatry related information on Igf2

• Overweight animals are hypophagic, suggesting that IGFII affects fat metabolism rather than feeding behavior in adult mice [5].
• Thus, these studies suggest that endogenously-produced IGF-II may stimulate muscle cell differentiation after both the decrease in Id and the induction of myogenin gene expression have occurred [6].

High impact information on Igf2

• Various chromatin models have been proposed that separate Igf2 and H19 into active and silent domains [7].
• Here we used a GAL4 knock-in approach as well as the chromosome conformation capture technique to show that the differentially methylated regions in the imprinted genes Igf2 and H19 interact in mice [7].
• CTCF maintains differential methylation at the Igf2/H19 locus [8].
• The unmethylated maternal ICR is a chromatin boundary that prevents distant enhancers from activating Igf2 (refs. 3-6) [8].
• Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on beta-cells [9].

Chemical compound and disease context of Igf2

• The effect of IGF-II was evoked at nonstimulatory concentrations of glucose, was mediated by a pertussis toxin sensitive GTP-binding protein, was dependent on protein kinase C-induced phosphorylation, and was independent of changes in cytoplasmic free Ca2+ concentration [10].
• Expression of IGF-II mRNA, however, was reduced in primary prostate cancer, metastatic lesions, and androgen-independent disease [11].
• Plasma corticosterone levels in these mice are twofold higher than in controls, in contrast to similar plasma ACTH levels, thus indicating a direct effect of IGF-II on adrenal cell hyperplasia and function [12].
• Stably transfected C2 muscle cell lines were established in which a mouse IGF-II cDNA was expressed in the antisense orientation relative to the constitutively active Moloney sarcoma virus promoter [13].
• By using phospholipid vesicles reconstituted with human wild type or mutant M6P/IGF II receptors and pertussis toxin-sensitive G-proteins, no stimulation of GTP gamma S binding to or GTPase activity of G(i)2, G(o)1, or G(i)/G(o) mixtures were observed in response to 1 microM IGF II [14].

Biological context of Igf2

• We also show that the mutant ICR lacks enhancer-blocking activity, as the expression of Igf2 is activated on mutant maternal chromosomes [8].
• These results reveal a mesodermal silencer, which may be regulated by methylation and which has a major role in H19-independent expression and imprinting control of Igf2 [15].
• The paternally expressed Igf2 encodes a potent fetal growth factor and the maternally expressed H19 encodes a non-coding RNA (refs 1,2) [15].
• Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19 [15].
• We have introduced Igf2 transgenes into the mouse genome by using embryonic stem cells, which leads to transactivation of the endogenous Igf2 gene [1].

Anatomical context of Igf2

• Here we show that deletion from the Igf2 gene of a transcript (P0) specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction [16].
• The closely linked H19 and Igf2 genes were activated after the blastocyst stage and often exhibited biallelic and monoallelic expression respectively in tissues of pregastrulation postimplantation-stage embryos, rather than reciprocal monoallelic modes as observed at later stages [17].
• Full restoration of monoallelic methylation and expression was imposed on H19, Igf2, and Igf2r upon germ-line transmission [18].
• These results establish that H19 and Igf2 utilize the same endoderm enhancers, but on different parental chromosomes [19].
• In addition, the deletion results in a minor relaxation of Igf2 imprinting in skeletal muscle and tongue [5].

Associations of Igf2 with chemical compounds

• The distal region of mouse chromosome 7 contains a cluster of imprinted genes that includes H19 and Igf2 (insulin-like growth factor 2) [20].
• Here, we show that placental transport of glucose and amino acids are increased in the Igf2 P0(+/-) null and that this up-regulation of transport occurs, at least in part, through increased expression of the transporter genes Slc2a3 and Slc38a4, the imprinted member of the System A amino acid transporter gene family [21].
• By using Southern blots and the bisulfite genomic-sequencing technique, we have investigated the allelic methylation patterns (epigenotypes) of the Igf2 gene in two strains of mouse with distinct deletions of the H19 gene [22].
• Dexamethasone at 100 nM increased Igf2 and type I IGF receptor mRNA levels in all genotypes [23].
• Modulation of Igf2 genomic imprinting in mice induced by 5-azacytidine, an inhibitor of DNA methylation [24].
• These morphological alterations may be the result of exposure to lower levels of glucocorticoids because plasma corticosterone levels were significantly lower in Igf2-/- mothers compared with wild-type controls [25].

Physical interactions of Igf2

• Decreasing fetal demand genetically by removal of fetal Igf2 abolished up-regulation of both transport systems and reduced placental System A amino acid transport activity and expression of Slc38a2 in late gestation [21].
• In most cells and tissues, IR binds IGF-II with relatively low affinity [26].
• Notable among this group were the growth factor gene Igf2 and its binding protein Igfbp5 [27].
• As R6 IGF-II binds with higher affinity to the type 2 receptor than canonical IGF-II or IGF-I, and insulin fails to interact, this suggests that the elevation of cyclic AMP in response to the other insulin related peptides (IRPs) is not through the type 2 receptor [28].
• Here we document that point mutations of the nucleotides in physical contact with CTCF within the endogenous H19 ICR lead to loss of CTCF binding and Igf2 imprinting only when passaged through the female germline [29].

Enzymatic interactions of Igf2

• The interactions between the enhancers and the genes are regulated by the DMR, which works as a selector by exerting dual functions: a methylated DMR on the paternal chromosome inactivates adjacent H19 and an unmethylated DMR on the maternal chromosome insulates Igf2 from the enhancers [30].

Regulatory relationships of Igf2

• Loss of the maternal H19 gene induces changes in Igf2 methylation in both cis and trans [22].
• In somatic cells, the maternally and paternally derived ICRs are hypo- and hypermethylated, respectively, with the former binding the insulator protein CCCTC-binding factor (CTCF) and acting to block access of enhancers to the Igf2 promoter [31].
• IGF-II is up-regulated and myofibres are hypertrophied in regenerating soleus of mice lacking FGF6 [32].
• In vitro TGFalpha treatment of mouse PE reactivated paternally expressed Igf2 gene in the PE and PP [33].
• PRL was most efficacious in stimulating IGF-II gene transcription from promoter 3 of the mouse IGF-II gene in vitro [34].

Other interactions of Igf2

• An enhancer deletion affects both H19 and Igf2 expression [19].
• The presence of a boundary element in this region has been suggested by observations of position-independent expression of H19 -containing transgenes and the blocking of accessibility of downstream enhancers to the upstream Igf2 and Ins2 genes on the maternal chromosome [35].
• Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II [26].
• Methylation caused the activation of the silent Igf2 allele in wild-type and Dnmt1 knockout cells, leading to biallelic Igf2 expression [36].
• Here we show that in the mouse mutant Minute (Mnt) the Igf2-H19 locus acquires a paternal methylation imprint in the maternal germline [37].

Analytical, diagnostic and therapeutic context of Igf2

• Combining allele-specific nuclear matrix binding assays and real-time PCR quantification, we show that retention of two of these Igf2 MARs (MAR0 and MAR2) in the nuclear matrix fraction depends on the tissue and is specific to the paternal allele [38].
• With in situ hybridization, we show that Igf2 was expressed in all adenoma irrespective of IGF-II supply [39].
• Reverse transcriptase polymerase chain reaction (RT-PCR) and restriction enzyme analysis confirmed that DEN treatment had indeed reactivated the hepatic expression of murine Igf2 in control mice in a dose-dependent manner [40].
• We have analysed the extent of non-imprinted expression of H19 and Igf2 in uniparental mouse embryonic stem (ES) cells during in vitro differentiation, and differentiation in teratomas using Northern blot and in situ hybridisation analysis [41].
• Its appearance in two independent animal models suggests that Igf2 may be important at pivotal checkpoints of hepatocarcinogenesis [40].

References