title: Disruption of mesodermal enhancers for Igf2 in the minute mutant.
abstract: The radiation-induced mutation minute (Mnt) in the mouse leads to intrauterine growth retardation with paternal transmission and has been linked to the distal chromosome 7 cluster of imprinted genes. We show that the mutation is an inversion, whose breakpoint distal to H19 disrupts and thus identifies an enhancer for Igf2 expression in skeletal muscle and tongue, and separates the gene from other mesodermal and extra-embryonic enhancers. Paternal transmission of Mnt leads to drastic downregulation of Igf2 transcripts in all mesodermal tissues and the placenta. Maternal transmission leads to methylation of the H19 differentially methylated region (DMR) and silencing of H19, showing that elements 3' of H19 can modify the maternal imprint. Methylation of the maternal DMR leads to biallelic expression of Igf2 in endodermal tissues and foetal overgrowth, demonstrating that methylation in vivo can open the chromatin boundary upstream of H19. Our work shows that most known enhancers for Igf2 are located 3' of H19 and establishes an important genetic paradigm for the inheritance of complex regulatory mutations in imprinted gene clusters.
authors.affiliation: Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, Babraham Institute, Cambridge CB2 4AT, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Davies
authors.forename: Lucy
authors.initials: L
authors.lastname: Bowden
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.forename: Wendy
authors.initials: W
authors.lastname: Dean
authors.forename: David
authors.initials: D
authors.lastname: Hill
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Furuumi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Bruce
authors.initials: B
authors.lastname: Cattanach
authors.forename: Wolf
authors.initials: W
authors.lastname: Reik
mesh_terms: D000818:Animals; D007446:Chromosome Inversion; D019175:DNA Methylation; D005314:Embryonic and Fetal Development / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000196:embryology / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D017404:In Situ Hybridization, Fluorescence; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D005810:Multigene Family; D009132:Muscles / Q000196:embryology; D009154:Mutation; D011247:Pregnancy; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics
chemical_list: C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II