Disruption of mesodermal enhancers for Igf2 in the minute mutant

Karen Davies, Lucy Bowden, Paul Smith, Wendy Dean, David Hill, Hiroyasu Furuumi, Hiroyuki Sasaki, Bruce Cattanach, Wolf Reik

Research output: Contribution to journalReview articlepeer-review

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1657-1668
Number of pages12
JournalDevelopment
Volume129
Issue number7
Publication statusPublished - Aug 23 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology

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