title: A skeletal muscle-specific mouse Igf2 repressor lies 40 kb downstream of the gene.
abstract: Igf2 and H19 are closely linked and reciprocally expressed genes on distal chromosome 7 in the mouse. We have previously shown that a 130 kb YAC transgene contains multiple tissue-specific enhancers for expression of both genes during embryogenesis. The YAC also contains all the crucial elements responsible for initiating and maintaining appropriate parent-of-origin-specific expression of these genes at ectopic sites, with expression of Igf2 after paternal inheritance and of H19 after maternal inheritance. Located centrally between Igf2 and H19 are two prominent DNaseI hypersensitive sites, and two stretches of sequence that are conserved between mouse and human. In this study, we have deleted, from the transgene, a one kb part of the intergenic region that contains the hypersensitive sites and one of the homologous stretches. We demonstrate that this deletion results in loss of maternal Igf2 repression in skeletal muscle cells, most strikingly in the tongue, late in embryogenesis. We propose that the intergenic region functions as a tissue-specific repressor element, forming an integral part of the complex regulatory mechanism that controls monoallelic gene expression in this domain.
authors.affiliation: Wellcome/CRC Institute of Cancer and Developmental Biology, and Physiological Laboratory, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK. jfxa1@mole.bio.cam.ac.uk
authors.forename: J F
authors.initials: JF
authors.lastname: Ainscough
authors.forename: R M
authors.initials: RM
authors.lastname: John
authors.forename: S C
authors.initials: SC
authors.lastname: Barton
authors.forename: M A
authors.initials: MA
authors.lastname: Surani
mesh_terms: D000483:Alleles; D000818:Animals; D001287:Attachment Sites, Microbiological / Q000235:genetics; D001483:Base Sequence; D021901:DNA, Intergenic / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D018392:Genomic Imprinting / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000196:embryology / Q000378:metabolism*; D009928:Organ Specificity; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D014059:Tongue / Q000196:embryology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D015017:Yolk Sac / Q000378:metabolism
chemical_list: D021901:DNA, Intergenic; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II; D003850:Deoxyribonuclease I