Tissue-specific and Mosaic Imprinting Defects Underlie Opposite Congenital Growth Disorders in Mice

Overview

Journal PLoS Genet

Specialty Genetics

Date 2018 Feb 23

PMID 29470501

Citations 8

Authors

Andrea Freschi

Stella K Hur

Federica Maria Valente

Folami Y Ideraabdullah

Angela Sparago

Maria Teresa Gentile

Andrea Oneglia

Diego Di Nucci

Luca Colucci-DAmato

Joanne L Thorvaldsen

Marisa S Bartolomei

Andrea Riccio

Flavia Cerrato

Affiliations

Soon will be listed here.

Abstract

Differential DNA methylation defects of H19/IGF2 are associated with congenital growth disorders 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. Furthermore, 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.

Citing Articles

Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith-Wiedemann syndrome-like overgrowth.

Hara S, Matsuhisa F, Kitajima S, Yatsuki H, Kubiura-Ichimaru M, Higashimoto K Commun Biol. 2024; 7(1):1605.

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Dysregulated expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models.

Chang S, Fulmer D, Hur S, Thorvaldsen J, Li L, Lan Y Elife. 2022; 11.

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The Role of Non-Coding RNAs in the Human Placenta.

Zarkovic M, Hufsky F, Markert U, Marz M Cells. 2022; 11(9).

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Exerts Maternal and Sexually Dimorphic Effects on Genomic Imprinting.

Xu Z, Shi J, Zhang Y, Liu Y, Zhao J, Chen Q Front Cell Dev Biol. 2022; 10:784128.

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The number of the CTCF binding sites of the H19/IGF2:IG-DMR correlates with DNA methylation and expression imprinting in a humanized mouse model.

Freschi A, Del Prete R, Pignata L, Cecere F, Manfrevola F, Mattia M Hum Mol Genet. 2021; 30(16):1509-1520.

PMID: 34132339 PMC: 8330897. DOI: 10.1093/hmg/ddab132.

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