Analyze Diet
Nucleic acids research1998; 26(7); 1605-1612; doi: 10.1093/nar/26.7.1605

A conserved structural element in horse and mouse IGF2 genes binds a methylation sensitive factor.

Abstract: The equine IGF2 gene has been cloned and characterised. It spans a 9 kb region, which is substantially less than the corresponding human gene. Three coding exons and three untranslated leader exons, all highly homologous to those in other species, were identified. Downstream of the polyadenylation site in exon 6, a dinucleotide repeat sequence was identified. Three putative promoters (P1-P3) were localised in the 5' region of the gene. RNase protection analysis revealed two active promoters in fetal tissues, P2 and P3, whereas P3 was the only promoter active in adult tissues. This represents a transcriptional pattern different from that in humans or rodents. A novel structural element, an inverted repeat, is predicted in the 3' region of the IGF2 gene. This repeat is conserved between species and located in a region which is differentially methylated in the human and mouse genes and might therefore be involved in the imprinting mechanism. The inverted repeat acquires a stem-loop structure in vitro with a hybrid A/B-DNA conformation in the stem area. Both in horse and mouse, a methylation-sensitive protein binds this structure with a strong requirement for the loop area. Furthermore, the protein might be developmentally regulated.
Publication Date: 1998-05-30 PubMed ID: 9512529PubMed Central: PMC147450DOI: 10.1093/nar/26.7.1605Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article discusses the structure and function of the IGF2 gene in horses, specifically how it interacts with a methylation sensitive factor through a unique structural element. The researchers found distinctions between the IGF2 gene in horses and those in other species, indicating different transcriptional patterns.

Background of the Research

  • The research is centered around the IGF2 gene in horses. The scientists have cloned and examined this gene, finding out that it spans a 9 kb region which is less significant than its human counterpart.
  • The horse IGF2 gene consists of three coding exons and three untranslated leader exons. These exons exhibit a high degree of homology with those of other species.
  • Located downstream of the polyadenylation site in exon 6 is a dinucleotide repeat sequence.
  • Three possible promoters (P1-P3) were located in the 5′ region of the gene.

Analyzing the IGF2 Gene

  • The team used RNase protection analysis, a laboratory method utilized to map the ends of RNA molecules, to identify the active promoters in fetal tissues and adult tissues.
  • Protein coding in fetal tissues was linked to promoters P2 and P3 while only promoter P3 was active in adult tissues, indicating a transcription pattern different from that in humans or rodents.
  • The researchers found a novel structural element, an inverted repeat, in the 3′ region of the IGF2 gene. This repeat appears conserved amongst species and is located in a part of the gene which is differentially methylated in the human and mouse genes.
  • The study postulates that the identified inverted repeat might have a role in the gene imprinting process.

Interacting with a Methylation Sensitive Factor

  • The inverted repeat within the IGF2 gene acquires a stem-loop structure when in vitro and has a hybrid A/B-DNA conformation in its stem area. This conformation is crucial for its interaction with a methylation-sensitive protein.
  • Both in the horse and mouse, a methylation-sensitive protein binds with the stem-loop structure, with a strong requirement for the loop area. This suggests a functional significance for this part of the gene.
  • Additionally, the researchers propose that the production of this methylation-sensitive protein might be affected by a developmental regulation mechanism.

Cite This Article

APA
Otte K, Choudhury D, Charalambous M, Engström W, Rozell B. (1998). A conserved structural element in horse and mouse IGF2 genes binds a methylation sensitive factor. Nucleic Acids Res, 26(7), 1605-1612. https://doi.org/10.1093/nar/26.7.1605

Publication

ISSN: 0305-1048
NlmUniqueID: 0411011
Country: England
Language: English
Volume: 26
Issue: 7
Pages: 1605-1612

Researcher Affiliations

Otte, K
  • Department of Pathology, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden. ko213@mole.biol.cam.ac.uk
Choudhury, D
    Charalambous, M
      Engström, W
        Rozell, B

          MeSH Terms

          • Animals
          • Base Sequence
          • Conserved Sequence
          • DNA / chemistry
          • DNA / genetics
          • DNA / metabolism
          • DNA Methylation
          • Exons
          • Fetus
          • Genomic Imprinting
          • Genomic Library
          • Horses / genetics
          • Humans
          • Insulin-Like Growth Factor II / biosynthesis
          • Insulin-Like Growth Factor II / genetics
          • Kidney / embryology
          • Kidney / metabolism
          • Liver / embryology
          • Liver / metabolism
          • Mice / genetics
          • Molecular Sequence Data
          • Nucleic Acid Conformation
          • Poly A
          • Promoter Regions, Genetic
          • Protein Sorting Signals / biosynthesis
          • Protein Sorting Signals / genetics
          • Repetitive Sequences, Nucleic Acid

          References

          This article includes 50 references
          1. Ohlsson R, Nyström A, Pfeifer-Ohlsson S, Töhönen V, Hedborg F, Schofield P, Flam F, Ekström TJ. IGF2 is parentally imprinted during human embryogenesis and in the Beckwith-Wiedemann syndrome.. Nat Genet 1993 May;4(1):94-7.
            pubmed: 8513333doi: 10.1038/ng0593-94google scholar: lookup
          2. Ward A. Beck-Wiedemann syndrome and Wilms' tumour.. Mol Hum Reprod 1997 Feb;3(2):157-68.
            pubmed: 9239720doi: 10.1093/molehr/3.2.157google scholar: lookup
          3. Schneid H, Seurin D, Vazquez MP, Gourmelen M, Cabrol S, Le Bouc Y. Parental allele specific methylation of the human insulin-like growth factor II gene and Beckwith-Wiedemann syndrome.. J Med Genet 1993 May;30(5):353-62.
            pubmed: 8320696doi: 10.1136/jmg.30.5.353google scholar: lookup
          4. Liu K, Miles HT, Frazier J, Sasisekharan V. A novel DNA duplex. A parallel-stranded DNA helix with Hoogsteen base pairing.. Biochemistry 1993 Nov 9;32(44):11802-9.
            pubmed: 8218251doi: 10.1021/bi00095a008google scholar: lookup
          5. Li E, Beard C, Jaenisch R. Role for DNA methylation in genomic imprinting.. Nature 1993 Nov 25;366(6453):362-5.
            pubmed: 8247133doi: 10.1038/366362a0google scholar: lookup
          6. Brandeis M, Kafri T, Ariel M, Chaillet JR, McCarrey J, Razin A, Cedar H. The ontogeny of allele-specific methylation associated with imprinted genes in the mouse.. EMBO J 1993 Sep;12(9):3669-77.
          7. Ohlsen SM, Lugenbeel KA, Wong EA. Characterization of the linked ovine insulin and insulin-like growth factor-II genes.. DNA Cell Biol 1994 Apr;13(4):377-88.
            pubmed: 8011164doi: 10.1089/dna.1994.13.377google scholar: lookup
          8. De Moor CH, Jansen M, Sussenbach JS, Van den Brande JL. Differential polysomal localization of human insulin-like-growth-factor-2 mRNAs in cell lines and foetal liver.. Eur J Biochem 1994 Jun 15;222(3):1017-24.
          9. Pedone PV, Cosma MP, Ungaro P, Colantuoni V, Bruni CB, Zarrilli R, Riccio A. Parental imprinting of rat insulin-like growth factor II gene promoters is coordinately regulated.. J Biol Chem 1994 Sep 30;269(39):23970-5.
            pubmed: 7929045
          10. Grabczyk E, Fishman MC. A long purine-pyrimidine homopolymer acts as a transcriptional diode.. J Biol Chem 1995 Jan 27;270(4):1791-7.
            pubmed: 7829515doi: 10.1074/jbc.270.4.1791google scholar: lookup
          11. Christiansen J, Kofod M, Nielsen FC. A guanosine quadruplex and two stable hairpins flank a major cleavage site in insulin-like growth factor II mRNA.. Nucleic Acids Res 1994 Dec 25;22(25):5709-16.
            pubmed: 7838726doi: 10.1093/nar/22.25.5709google scholar: lookup
          12. Otte K, Engström W. Insulin-like growth factor II in the horse: determination of a cDNA nucleotide sequence and expression in fetal and adult tissue.. Gen Comp Endocrinol 1994 Nov;96(2):270-5.
            pubmed: 7851727doi: 10.1006/gcen.1994.1182google scholar: lookup
          13. Newell S, Ward A, Graham C. Discriminating translation of insulin-like growth factor-II (IGF-II) during mouse embryogenesis.. Mol Reprod Dev 1994 Nov;39(3):249-58.
            pubmed: 7888164doi: 10.1002/mrd.1080390302google scholar: lookup
          14. Neumann B, Kubicka P, Barlow DP. Characteristics of imprinted genes.. Nat Genet 1995 Jan;9(1):12-3.
            pubmed: 7704015doi: 10.1038/ng0195-12google scholar: lookup
          15. Feil R, Walter J, Allen ND, Reik W. Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes.. Development 1994 Oct;120(10):2933-43.
            pubmed: 7607083doi: 10.1242/dev.120.10.2933google scholar: lookup
          16. Kalb VF Jr, Bernlohr RW. A new spectrophotometric assay for protein in cell extracts.. Anal Biochem 1977 Oct;82(2):362-71.
            pubmed: 20815doi: 10.1016/0003-2697(77)90173-7google scholar: lookup
          17. Rinderknecht E, Humbel RE. Primary structure of human insulin-like growth factor II.. FEBS Lett 1978 May 15;89(2):283-6.
            pubmed: 658418doi: 10.1016/0014-5793(78)80237-3google scholar: lookup
          18. Rosenberg M, Court D. Regulatory sequences involved in the promotion and termination of RNA transcription.. Annu Rev Genet 1979;13:319-53.
          19. Blundell TL, Humbel RE. Hormone families: pancreatic hormones and homologous growth factors.. Nature 1980 Oct 30;287(5785):781-7.
            pubmed: 6107857doi: 10.1038/287781a0google scholar: lookup
          20. Riazance JH, Baase WA, Johnson WC Jr, Hall K, Cruz P, Tinoco I Jr. Evidence for Z-form RNA by vacuum UV circular dichroism.. Nucleic Acids Res 1985 Jul 11;13(13):4983-9.
            pubmed: 2410859doi: 10.1093/nar/13.13.4983google scholar: lookup
          21. Frunzio R, Chiariotti L, Brown AL, Graham DE, Rechler MM, Bruni CB. Structure and expression of the rat insulin-like growth factor II (rIGF-II) gene. rIGF-II RNAs are transcribed from two promoters.. J Biol Chem 1986 Dec 25;261(36):17138-49.
            pubmed: 3023383
          22. de Pagter-Holthuizen P, Jansen M, van Schaik FM, van der Kammen R, Oosterwijk C, Van den Brande JL, Sussenbach JS. The human insulin-like growth factor II gene contains two development-specific promoters.. FEBS Lett 1987 Apr 20;214(2):259-64.
            pubmed: 3569524doi: 10.1016/0014-5793(87)80066-2google scholar: lookup
          23. Soares MB, Turken A, Ishii D, Mills L, Episkopou V, Cotter S, Zeitlin S, Efstratiadis A. Rat insulin-like growth factor II gene. A single gene with two promoters expressing a multitranscript family.. J Mol Biol 1986 Dec 20;192(4):737-52.
            pubmed: 2438416doi: 10.1016/0022-2836(86)90025-2google scholar: lookup
          24. Ueno T, Takahashi K, Matsuguchi T, Endo H, Yamamoto M. A new leader exon identified in the rat insulin-like growth factor II gene.. Biochem Biophys Res Commun 1987 Oct 14;148(1):344-9.
            pubmed: 3453119doi: 10.1016/0006-291x(87)91116-8google scholar: lookup
          25. Horwitz MS, Loeb LA. An E. coli promoter that regulates transcription by DNA superhelix-induced cruciform extrusion.. Science 1988 Aug 5;241(4866):703-5.
            pubmed: 2456617doi: 10.1126/science.2456617google scholar: lookup
          26. de Pagter-Holthuizen P, Jansen M, van der Kammen RA, van Schaik FM, Sussenbach JS. Differential expression of the human insulin-like growth factor II gene. Characterization of the IGF-II mRNAs and an mRNA encoding a putative IGF-II-associated protein.. Biochim Biophys Acta 1988 Sep 7;950(3):282-95.
            pubmed: 3167054doi: 10.1016/0167-4781(88)90124-8google scholar: lookup
          27. Schofield PN, Tate VE. Regulation of human IGF-II transcription in fetal and adult tissues.. Development 1987 Dec;101(4):793-803.
            pubmed: 3503697doi: 10.1242/dev.101.4.793google scholar: lookup
          28. Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations.. Endocr Rev 1989 Feb;10(1):68-91.
            pubmed: 2666112doi: 10.1210/edrv-10-1-68google scholar: lookup
          29. DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting.. Nature 1990 May 3;345(6270):78-80.
            pubmed: 2330056doi: 10.1038/345078a0google scholar: lookup
          30. Manzini G, Xodo LE, Gasparotto D, Quadrifoglio F, van der Marel GA, van Boom JH. Triple helix formation by oligopurine-oligopyrimidine DNA fragments. Electrophoretic and thermodynamic behavior.. J Mol Biol 1990 Jun 20;213(4):833-43.
            pubmed: 2359124doi: 10.1016/S0022-2836(05)80267-0google scholar: lookup
          31. Nielsen FC, Gammeltoft S, Christiansen J. Translational discrimination of mRNAs coding for human insulin-like growth factor II.. J Biol Chem 1990 Aug 15;265(23):13431-4.
            pubmed: 1696253
          32. Ikejiri K, Ueno T, Matsuguchi T, Takahashi K, Endo H, Yamamoto M. The primary structure of the rat insulin-like growth factor II gene region.. Biochim Biophys Acta 1990 Jul 30;1049(3):350-3.
            pubmed: 2383591doi: 10.1016/0167-4781(90)90110-ngoogle scholar: lookup
          33. Holthuizen P, van der Lee FM, Ikejiri K, Yamamoto M, Sussenbach JS. Identification and initial characterization of a fourth leader exon and promoter of the human IGF-II gene.. Biochim Biophys Acta 1990 Nov 30;1087(3):341-3.
            pubmed: 2248982doi: 10.1016/0167-4781(90)90010-ygoogle scholar: lookup
          34. Rotwein P, Hall LJ. Evolution of insulin-like growth factor II: characterization of the mouse IGF-II gene and identification of two pseudo-exons.. DNA Cell Biol 1990 Dec;9(10):725-35.
            pubmed: 1702294doi: 10.1089/dna.1990.9.725google scholar: lookup
          35. McMurray CT, Wilson WD, Douglass JO. Hairpin formation within the enhancer region of the human enkephalin gene.. Proc Natl Acad Sci U S A 1991 Jan 15;88(2):666-70.
            pubmed: 1988963doi: 10.1073/pnas.88.2.666google scholar: lookup
          36. DeChiara TM, Robertson EJ, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene.. Cell 1991 Feb 22;64(4):849-59.
            pubmed: 1997210doi: 10.1016/0092-8674(91)90513-xgoogle scholar: lookup
          37. Moore T, Constancia M, Zubair M, Bailleul B, Feil R, Sasaki H, Reik W. Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2.. Proc Natl Acad Sci U S A 1997 Nov 11;94(23):12509-14.
            pubmed: 9356480doi: 10.1073/pnas.94.23.12509google scholar: lookup
          38. Zazopoulos E, Lalli E, Stocco DM, Sassone-Corsi P. DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis.. Nature 1997 Nov 20;390(6657):311-5.
            pubmed: 9384387doi: 10.1038/36899google scholar: lookup
          39. Ikejiri K, Furuichi M, Ueno T, Matsuguchi T, Takahashi K, Endo H, Yamamoto M. The presence and active transcription of three independent leader exons in the mouse insulin-like growth factor II gene.. Biochim Biophys Acta 1991 May 2;1089(1):77-82.
            pubmed: 2025650doi: 10.1016/0167-4781(91)90087-3google scholar: lookup
          40. Ikejiri K, Wasada T, Haruki K, Hizuka N, Hirata Y, Yamamoto M. Identification of a novel transcription unit in the human insulin-like growth factor-II gene.. Biochem J 1991 Dec 1;280 ( Pt 2)(Pt 2):439-44.
            pubmed: 1720956doi: 10.1042/bj2800439google scholar: lookup
          41. van Dijk MA, van Schaik FM, Bootsma HJ, Holthuizen P, Sussenbach JS. Initial characterization of the four promoters of the human insulin-like growth factor II gene.. Mol Cell Endocrinol 1991 Oct;81(1-3):81-94.
            pubmed: 1797589doi: 10.1016/0303-7207(91)90207-9google scholar: lookup
          42. Sasaki H, Jones PA, Chaillet JR, Ferguson-Smith AC, Barton SC, Reik W, Surani MA. Parental imprinting: potentially active chromatin of the repressed maternal allele of the mouse insulin-like growth factor II (Igf2) gene.. Genes Dev 1992 Oct;6(10):1843-56.
            pubmed: 1383088doi: 10.1101/gad.6.10.1843google scholar: lookup
          43. Spiro C, Richards JP, Chandrasekaran S, Brennan RG, McMurray CT. Secondary structure creates mismatched base pairs required for high-affinity binding of cAMP response element-binding protein to the human enkephalin enhancer.. Proc Natl Acad Sci U S A 1993 May 15;90(10):4606-10.
            pubmed: 8506306doi: 10.1073/pnas.90.10.4606google scholar: lookup
          44. Nielsen FC, Ostergaard L, Nielsen J, Christiansen J. Growth-dependent translation of IGF-II mRNA by a rapamycin-sensitive pathway.. Nature 1995 Sep 28;377(6547):358-62.
            pubmed: 7566093doi: 10.1038/377358a0google scholar: lookup
          45. Banerjee S, Smallwood A. A chromatin model of IGF2/H19 imprinting.. Nat Genet 1995 Nov;11(3):237-8.
            pubmed: 7581444doi: 10.1038/ng1195-237google scholar: lookup
          46. Jin IH, Sinha G, Yballe C, Vu TH, Hoffman AR. The human insulin-like growth factor-II promoter P1 is not restricted to liver: evidence for expression of P1 in other tissues and for a homologous promoter in baboon liver.. Horm Metab Res 1995 Oct;27(10):447-9.
            pubmed: 8575722doi: 10.1055/s-2007-979999google scholar: lookup
          47. Scheper W, Holthuizen PE, Sussenbach JS. The cis-acting elements involved in endonucleolytic cleavage of the 3' UTR of human IGF-II mRNAs bind a 50 kDa protein.. Nucleic Acids Res 1996 Mar 15;24(6):1000-7.
            pubmed: 8604329doi: 10.1093/nar/24.6.1000google scholar: lookup
          48. Li X, Cui H, Sandstedt B, Nordlinder H, Larsson E, Ekström TJ. Expression levels of the insulin-like growth factor-II gene (IGF2) in the human liver: developmental relationships of the four promoters.. J Endocrinol 1996 Apr;149(1):117-24.
            pubmed: 8676043doi: 10.1677/joe.0.1490117google scholar: lookup
          49. Pearson CE, Zorbas H, Price GB, Zannis-Hadjopoulos M. Inverted repeats, stem-loops, and cruciforms: significance for initiation of DNA replication.. J Cell Biochem 1996 Oct;63(1):1-22.
          50. Giannoukakis N, Deal C, Paquette J, Goodyer CG, Polychronakos C. Parental genomic imprinting of the human IGF2 gene.. Nat Genet 1993 May;4(1):98-101.
            pubmed: 8099843doi: 10.1038/ng0593-98google scholar: lookup

          Citations

          This article has been cited 5 times.
          1. Kikuchi K, Sasaki K, Akizawa H, Tsukahara H, Bai H, Takahashi M, Nambo Y, Hata H, Kawahara M. Identification and expression analysis of cDNA encoding insulin-like growth factor 2 in horses. J Reprod Dev 2018 Feb 27;64(1):57-64.
            doi: 10.1262/jrd.2017-124pubmed: 29151450google scholar: lookup
          2. Tobi EW, Slagboom PE, van Dongen J, Kremer D, Stein AD, Putter H, Heijmans BT, Lumey LH. Prenatal famine and genetic variation are independently and additively associated with DNA methylation at regulatory loci within IGF2/H19. PLoS One 2012;7(5):e37933.
            doi: 10.1371/journal.pone.0037933pubmed: 22666415google scholar: lookup
          3. Simmgen M, Knauf C, Lopez M, Choudhury AI, Charalambous M, Cantley J, Bedford DC, Claret M, Iglesias MA, Heffron H, Cani PD, Vidal-Puig A, Burcelin R, Withers DJ. Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice. Diabetologia 2006 Mar;49(3):552-61.
            doi: 10.1007/s00125-005-0084-4pubmed: 16404553google scholar: lookup
          4. Weidman JR, Murphy SK, Nolan CM, Dietrich FS, Jirtle RL. Phylogenetic footprint analysis of IGF2 in extant mammals. Genome Res 2004 Sep;14(9):1726-32.
            doi: 10.1101/gr.2774804pubmed: 15342558google scholar: lookup
          5. Engström W, Shokrai A, Otte K, Granérus M, Gessbo A, Bierke P, Madej A, Sjölund M, Ward A. Transcriptional regulation and biological significance of the insulin like growth factor II gene. Cell Prolif 1998 Oct-Dec;31(5-6):173-89.