title: Epigenetic regulation of the Igf2/H19 gene cluster.
abstract: Igf2 (insulin-like growth factor 2) and H19 genes are imprinted in mammals; they are expressed unevenly from the two parental alleles. Igf2 is a growth factor expressed in most normal tissues, solely from the paternal allele. H19 gene is transcribed (but not translated to a protein) from the maternal allele. Igf2 protein is a growth factor particularly important during pregnancy, where it promotes both foetal and placental growth and also nutrient transfer from mother to offspring via the placenta. This article reviews epigenetic regulation of the Igf2/H19 gene-cluster that leads to parent-specific expression, with current models including parental allele-specific DNA methylation and chromatin modifications, DNA-binding of insulator proteins (CTCFs) and three-dimensional partitioning of DNA in the nucleus. It is emphasized that key genomic features are conserved among mammals and have been functionally tested in mouse. 'The enhancer competition model', 'the boundary model' and 'the chromatin-loop model' are three models based on differential methylation as the epigenetic mark responsible for the imprinted expression pattern. Pathways are discussed that can account for allelic methylation differences; there is a recent study that contradicts the previously accepted fact that biallelic expression is accompanied with loss of differential methylation pattern.
authors.affiliation: Faculty of Veterinary Medicine, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, 75007, Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Nordin
authors.forename: D
authors.initials: D
authors.lastname: Bergman
authors.forename: M
authors.initials: M
authors.lastname: Halje
authors.forename: W
authors.initials: W
authors.lastname: Engström
authors.forename: A
authors.initials: A
authors.lastname: Ward
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005810:Multigene Family; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism
chemical_list: C094335:H19 long non-coding RNA; D007328:Insulin; D062085:RNA, Long Noncoding; D007335:Insulin-Like Growth Factor II
references.citation: J Cell Sci. 1985 Feb;73:361-73
references.pmid: 2991306
references.citation: J Cell Sci. 1988 Jul;90 ( Pt 3):475-84
references.pmid: 3253292
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D188-94
references.pmid: 23193294
references.citation: Mol Cell. 2013 Oct 10;52(1):101-12
references.pmid: 24055342
references.citation: Mech Dev. 2002 Sep;117(1-2):15-23
references.pmid: 12204247
references.citation: Cytogenet Genome Res. 2006;113(1-4):188-93
references.pmid: 16575179
references.citation: Gen Comp Endocrinol. 1994 Nov;96(2):270-5
references.pmid: 7851727
references.citation: Cytogenet Genome Res. 2006;113(1-4):279-91
references.pmid: 16575191
references.citation: FEBS Lett. 1987 Apr 20;214(2):259-64
references.pmid: 3569524
references.citation: FEBS Lett. 1999 Sep 10;458(1):45-50
references.pmid: 10518931
references.citation: PLoS One. 2007 Sep 05;2(9):e845
references.pmid: 17786216
references.citation: Int J Dev Biol. 1993 Mar;37(1):25-31
references.pmid: 8389579
references.citation: PLoS Genet. 2009 Nov;5(11):e1000739
references.pmid: 19956766
references.citation: Genes Dev. 1995 Sep 1;9(17):2079-89
references.pmid: 7544754
references.citation: Dev Cell. 2010 Nov 16;19(5):675-86
references.pmid: 21074718
references.citation: Nat Genet. 1993 Sep;5(1):74-8
references.pmid: 8220428
references.citation: Mol Cell Biol. 2008 Jan;28(1):71-82
references.pmid: 17967893
references.citation: Clin Genet. 2011 Jul;80(1):83-8
references.pmid: 20738330
references.citation: Genome Biol. 2013 Jul 29;14(7):126
references.pmid: 23899167
references.citation: Genes Dev. 1992 Oct;6(10):1843-56
references.pmid: 1383088
references.citation: Nat Genet. 2004 Aug;36(8):889-93
references.pmid: 15273689
references.citation: Dev Biol. 1996 Aug 1;177(2):517-35
references.pmid: 8806828
references.citation: In Vivo. 2012 Jul-Aug;26(4):519-26
references.pmid: 22773563
references.citation: Mol Cell Biol. 2006 Feb;26(4):1245-58
references.pmid: 16449639
references.citation: Nature. 1984 Apr 5-11;308(5959):548-50
references.pmid: 6709062
references.citation: Cytokine Growth Factor Rev. 2008 Apr;19(2):111-20
references.pmid: 18308616
references.citation: Genomics. 2004 Dec;84(6):952-60
references.pmid: 15533712
references.citation: Genes Dev. 1994 Dec 15;8(24):2953-63
references.pmid: 8001817
references.citation: Nature. 1995 May 4;375(6526):34-9
references.pmid: 7536897
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12417-22
references.pmid: 18719115
references.citation: Hum Mol Genet. 2006 Apr 15;15(8):1259-69
references.pmid: 16531418
references.citation: Nature. 2002 Jun 27;417(6892):945-8
references.pmid: 12087403
references.citation: Hum Mol Genet. 2000 Nov 22;9(19):2885-94
references.pmid: 11092765
references.citation: Development. 2006 Sep;133(17):3411-8
references.pmid: 16887828
references.citation: Nature. 2000 May 25;405(6785):482-5
references.pmid: 10839546
references.citation: J Embryol Exp Morphol. 1986 Nov;98:71-83
references.pmid: 3655653
references.citation: Mol Hum Reprod. 1997 Feb;3(2):157-68
references.pmid: 9239720
references.citation: Development. 1994 Feb;120(2):361-8
references.pmid: 8149914
references.citation: Cell. 2013 Mar 14;152(6):1285-97
references.pmid: 23498937
references.citation: Reproduction. 2013 Apr 29;145(5):R117-37
references.pmid: 23445556
references.citation: Hum Mol Genet. 2003 Feb 1;12(3):283-94
references.pmid: 12554682
references.citation: Nature. 1990 May 3;345(6270):78-80
references.pmid: 2330056
references.citation: Gerontology. 2013;59(3):240-9
references.pmid: 23257688
references.citation: Development. 2009 Oct;136(20):3413-21
references.pmid: 19762426
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10365-9
references.pmid: 7524092
references.citation: Cancer Res. 1994 May 15;54(10):2560-2
references.pmid: 8168079
references.citation: Cell. 1991 Feb 22;64(4):849-59
references.pmid: 1997210
references.citation: Philos Trans R Soc Lond B Biol Sci. 2006 Dec 29;361(1476):2229-37
references.pmid: 17118935
references.citation: Nat Cell Biol. 2012 Jun 10;14(7):659-65
references.pmid: 22684254
references.citation: Genes Dev. 1998 Dec 1;12(23):3693-702
references.pmid: 9851976
references.citation: Dev Biol. 2004 Jul 15;271(2):488-97
references.pmid: 15223349
references.citation: Br J Cancer. 1995 Nov;72(5):1189-93
references.pmid: 7577466
references.citation: Curr Opin Genet Dev. 1998 Dec;8(6):701-8
references.pmid: 9914201
references.citation: Cell. 1991 Mar 22;64(6):1045-6
references.pmid: 1848481
references.citation: Nature. 1993 Oct 21;365(6448):764-7
references.pmid: 7692308
references.citation: Nat Rev Genet. 2001 Jan;2(1):21-32
references.pmid: 11253064
references.citation: Ann N Y Acad Sci. 2000 Apr;907:149-63
references.pmid: 10818626
references.citation: Dev Biol. 2010 Jan 1;337(1):1-8
references.pmid: 19833122
references.citation: Carcinogenesis. 2010 Mar;31(3):350-8
references.pmid: 19926638
references.citation: Cell Prolif. 1998 Oct-Dec;31(5-6):173-89
references.pmid: 9925986
references.citation: Nature. 2012 Apr 11;485(7398):376-80
references.pmid: 22495300
references.citation: Nature. 2000 May 25;405(6785):486-9
references.pmid: 10839547
references.citation: Eur J Pediatr. 1989 Jan;148(4):320-4
references.pmid: 2565235
references.citation: Genome Res. 2012 Sep;22(9):1680-8
references.pmid: 22955980
references.citation: Mech Dev. 2003 Dec;120(12):1433-42
references.pmid: 14654216
references.citation: Mol Cell Biol. 1990 Jan;10(1):28-36
references.pmid: 1688465
references.citation: Proc Biol Sci. 2003 Aug 7;270 Suppl 1:S100-3
references.pmid: 12952649
references.citation: BMC Genet. 2011 May 17;12:47
references.pmid: 21575277
references.citation: Genes Dev. 1993 Sep;7(9):1663-73
references.pmid: 7690336
references.citation: Genes Cells. 2000 Aug;5(8):649-59
references.pmid: 10947850