Lecture8.pdf - RESEARCH ARTICLE Tissue-specific and mosaic...

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RESEARCH ARTICLE Tissue-specific and mosaic imprinting defects underlie opposite congenital growth disorders in mice Andrea Freschi 1 , Stella K. Hur 2 , Federica Maria Valente 1 , Folami Y. Ideraabdullah 3,4 , Angela Sparago 1 , Maria Teresa Gentile 1 , Andrea Oneglia 1,5 , Diego Di Nucci 6 , Luca Colucci-D’Amato 1 , Joanne L. Thorvaldsen 2 , Marisa S. Bartolomei 2 * , Andrea Riccio 1,5 * , Flavia Cerrato 1 * 1 Department of Environmental Technologies, Biological and Pharmaceutical Sciences, University of Campania, “Luigi Vanvitelli”, Naples, Italy, 2 Epigenetics Institute, Department of Cell & Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 3 Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America, 4 Department of Nutrition, Gillings School of Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America, 5 Institute of Genetics and Biophysics, “Adriano Buzzati Traverso” - CNR, Naples, Italy, 6 Department of Experimental Medicine, University of Campania, “Luigi Vanvitelli”, Naples, Italy * [email protected] (MSB); [email protected] (AR); [email protected] (FC) Abstract Differential DNA methylation defects of H19/IGF2 are associated with congenital growth dis- orders characterized by opposite clinical pictures. Due to structural differences between human and mouse, the mechanisms by which mutations of the H19/IGF2 Imprinting Control region (IC1) result in these diseases are undefined. To address this issue, we previously generated a mouse line carrying a humanized IC1 (hIC1) and now replaced the wildtype with a mutant IC1 identified in the overgrowth-associated Beckwith-Wiedemann syndrome. The new humanized mouse line shows pre/post-natal overgrowth on maternal transmission and pre/post-natal undergrowth on paternal transmission of the mutation. The mutant hIC1 acquires abnormal methylation during development causing opposite H19/Igf2 imprinting defects on maternal and paternal chromosomes. Differential and possibly mosaic Igf2 expression and imprinting is associated with asymmetric growth of bilateral organs. Further- more, tissue-specific imprinting defects result in deficient liver- and placenta-derived Igf2 on paternal transmission and excessive Igf2 in peripheral tissues on maternal transmission, providing a possible molecular explanation for imprinting-associated and phenotypically contrasting growth disorders. Author summary A humanized mouse line carrying a mutation of the H19/IGF2 imprinting control region demonstrates how tissue-specific and mosaic imprinting alterations result in growth dis- orders with opposite clinical pictures and asymmetric growth of bilateral organs.
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