title: The interval between Ins2 and Ascl2 is dispensable for imprinting centre function in the murine Beckwith-Wiedemann region.
abstract: Imprinted genes are commonly clustered in domains across the mammalian genome, suggesting a degree of coregulation via long-range coordination of their monoallelic transcription. The distal end of mouse chromosome 7 (Chr 7) contains two clusters of imprinted genes within a approximately 1 Mb domain. This region is conserved on human 11p15.5 where it is implicated in the Beckwith-Wiedemann syndrome. In both species, imprinted regulation requires two critical cis-acting imprinting centres, carrying different germline epigenetic marks and mediating imprinted expression in the proximal and distal sub-domains. The clusters are separated by a region containing the gene for tyrosine hydroxylase (Th) as well as a high density of short repeats and retrotransposons in the mouse. We have used the Cre-loxP recombination system in vivo to engineer an interstitial deletion of this approximately 280-kb intervening region previously proposed to participate in the imprinting mechanism or to act as a boundary between the two sub-domains. The deletion allele, Del(7AI), is silent with respect to epigenetic marking at the two flanking imprinting centres. Reciprocal inheritance of Del(7AI) demonstrates that the deleted region, which represents more than a quarter of the previously defined imprinted domain, is associated with intrauterine growth restriction in maternal heterozygotes. In homozygotes, the deficiency behaves as a Th null allele and can be rescued pharmacologically by bypassing the metabolic requirement for TH in utero. Our results show that the deleted interval is not required for normal imprinting on distal Chr 7 and uncover a new imprinted growth phenotype.
authors.affiliation: Department of Medical Genetics and Molecular Epigenetics Group, Life Sciences Institute, The University of British Columbia, Vancouver, BC, Canada. louis.lefebvre@ubc.ca
authors.forename: Louis
authors.initials: L
authors.lastname: Lefebvre
authors.forename: Lynn
authors.initials: L
authors.lastname: Mar
authors.forename: Aaron
authors.initials: A
authors.lastname: Bogutz
authors.forename: Rosemary
authors.initials: R
authors.lastname: Oh-McGinnis
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Mandegar
authors.forename: Jana
authors.initials: J
authors.lastname: Paderova
authors.forename: Marina
authors.initials: M
authors.lastname: Gertsenstein
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics* / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D018392:Genomic Imprinting; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007328:Insulin; C489311:Ascl2 protein, mouse
references.citation: Genes Dev. 2005 Dec 1;19(23):2862-76
references.pmid: 16322559
references.citation: Nat Genet. 1995 Apr;9(4):407-13
references.pmid: 7795647
references.citation: BMC Evol Biol. 2008 May 29;8:163
references.pmid: 18510768
references.citation: Hum Mol Genet. 2005 Feb 15;14(4):503-11
references.pmid: 15640248
references.citation: Genomics. 1999 May 15;58(1):18-28
references.pmid: 10331941
references.citation: Nature. 1997 May 8;387(6629):151-8
references.pmid: 9144284
references.citation: Genes Dev. 1998 Dec 1;12(23):3693-702
references.pmid: 9851976
references.citation: BMC Dev Biol. 2007 May 21;7:53
references.pmid: 17517131
references.citation: Nat Genet. 2006 Nov;38(11):1341-7
references.pmid: 17033624
references.citation: Genome Res. 2000 Nov;10(11):1697-710
references.pmid: 11076855
references.citation: Nucleic Acids Res. 2006 Jul 19;34(12):e88
references.pmid: 16855283
references.citation: Nature. 1995 Apr 13;374(6523):640-3
references.pmid: 7715703
references.citation: Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R61-8
references.pmid: 12668598
references.citation: Nat Genet. 2002 Nov;32(3):426-31
references.pmid: 12410230
references.citation: Gene. 1991 Dec 15;108(2):193-9
references.pmid: 1660837
references.citation: Hum Mol Genet. 1998 Jul;7(7):1149-59
references.pmid: 9618174
references.citation: Hum Mol Genet. 2000 Nov 1;9(18):2691-706
references.pmid: 11063728
references.citation: Transgenic Res. 2004 Jun;13(3):289-94
references.pmid: 15359605
references.citation: Nat Genet. 1993 May;4(1):98-101
references.pmid: 8099843
references.citation: Nature. 1994 Sep 22;371(6495):333-6
references.pmid: 8090202
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8424-8
references.pmid: 8378314
references.citation: Genome Res. 2005 Jan;15(1):146-53
references.pmid: 15590939
references.citation: Nature. 2002 Jun 27;417(6892):945-8
references.pmid: 12087403
references.citation: Nature. 2000 May 25;405(6785):482-5
references.pmid: 10839546
references.citation: Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8064-9
references.pmid: 10393948
references.citation: DNA Res. 2004 Oct 31;11(5):325-34
references.pmid: 15747580
references.citation: Nat Genet. 1998 Dec;20(4):381-4
references.pmid: 9843213
references.citation: Methods Enzymol. 1993;225:890-900
references.pmid: 8231893
references.citation: Nat Genet. 1993 May;4(1):94-7
references.pmid: 8513333
references.citation: Nat Genet. 1994 Mar;6(3):310-3
references.pmid: 8012396
references.citation: Hum Mol Genet. 2000 Jul 22;9(12):1829-41
references.pmid: 10915772
references.citation: Curr Biol. 2000 May 18;10(10):607-10
references.pmid: 10837224
references.citation: Development. 1997 Sep;124(18):3621-32
references.pmid: 9342054
references.citation: Diabetes. 2001 Jan;50(1):199-203
references.pmid: 11147788
references.citation: Genomics. 1998 Jan 1;47(1):52-7
references.pmid: 9465295
references.citation: Genes Dev. 2000 May 15;14(10):1186-95
references.pmid: 10817754
references.citation: Nat Genet. 1995 Oct;11(2):204-6
references.pmid: 7550351
references.citation: Mamm Genome. 1999 Feb;10(2):182-5
references.pmid: 9922400
references.citation: Genes Dev. 1997 Apr 15;11(8):973-83
references.pmid: 9136926
references.citation: J Clin Invest. 2000 Feb;105(3):247-52
references.pmid: 10675349
references.citation: Diabetes. 2001 Feb;50 Suppl 1:S150-3
references.pmid: 11272179
references.citation: Mol Cell Biol. 2002 Apr;22(8):2450-62
references.pmid: 11909940
references.citation: Hum Genet. 1995 Jan;95(1):123-5
references.pmid: 7814018
references.citation: J Biol Chem. 1995 Nov 10;270(45):27235-43
references.pmid: 7592982
references.citation: Cell. 1991 Feb 22;64(4):849-59
references.pmid: 1997210
references.citation: Mol Reprod Dev. 1998 Nov;51(3):274-80
references.pmid: 9771647
references.citation: Nature. 2000 May 25;405(6785):486-9
references.pmid: 10839547
references.citation: Mol Biol Evol. 1998 Nov;15(11):1373-80
references.pmid: 12572601
references.citation: Genome Res. 2005 Jan;15(1):154-65
references.pmid: 15590938
references.citation: Annu Rev Cell Dev Biol. 2003;19:237-59
references.pmid: 14570570
references.citation: Mol Cell Biol. 2008 Feb;28(3):1092-103
references.pmid: 18039841
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7490-5
references.pmid: 12032310
references.citation: Nat Genet. 1995 Mar;9(3):235-42
references.pmid: 7773285
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5203-8
references.pmid: 10220444
references.citation: Nature. 1993 Apr 22;362(6422):751-5
references.pmid: 8469285
references.citation: Bioinformatics. 2005 Nov 1;21(21):4067-8
references.pmid: 16141249
references.citation: Genes Dev. 1993 Sep;7(9):1663-73
references.pmid: 7690336
references.citation: Proc Natl Acad Sci U S A. 1997 May 13;94(10):5137-40
references.pmid: 9144203
references.citation: Hum Mol Genet. 2001 Jul 15;10(15):1601-9
references.pmid: 11468278