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组织特异性和镶嵌印迹缺陷是导致小鼠相反先天性生长障碍的基础。

Tissue-specific and mosaic imprinting defects underlie opposite congenital growth disorders in mice.

机构信息

Department of Environmental Technologies, Biological and Pharmaceutical Sciences, University of Campania, "Luigi Vanvitelli", Naples, Italy.

Epigenetics Institute, Department of Cell & Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

出版信息

PLoS Genet. 2018 Feb 22;14(2):e1007243. doi: 10.1371/journal.pgen.1007243. eCollection 2018 Feb.

DOI:10.1371/journal.pgen.1007243
PMID:29470501
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5839592/
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.

摘要

H19/IGF2 的差异 DNA 甲基化缺陷与以相反临床表现为特征的先天性生长障碍有关。由于人类和小鼠之间的结构差异，导致 H19/IGF2 印迹控制区（IC1）突变导致这些疾病的机制尚不清楚。为了解决这个问题，我们之前生成了携带人源化 IC1（hIC1）的小鼠品系，现在用在与过度生长相关的 Beckwith-Wiedemann 综合征中发现的突变 IC1 替换了野生型。新的人源化小鼠品系在母系传递时表现出产前和产后过度生长，在父系传递时表现出产前和产后生长不足。突变的 hIC1 在发育过程中获得异常甲基化，导致母系和父系染色体上 H19/Igf2 印记缺陷相反。差异和可能的镶嵌 Igf2 表达和印记与双侧器官的不对称生长有关。此外，组织特异性印记缺陷导致父系传递时肝脏和胎盘来源的 Igf2 缺乏，以及母系传递时外周组织中 Igf2 过多，为印记相关和表型对比生长障碍提供了可能的分子解释。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/594973095d61/pgen.1007243.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/791e9b1e56fb/pgen.1007243.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/9fc1b9b4acf4/pgen.1007243.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/cc3a6e882928/pgen.1007243.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/4678e40d4d6a/pgen.1007243.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/2955fe13199f/pgen.1007243.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/9a5f78b12694/pgen.1007243.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/69b44c095be0/pgen.1007243.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/d7f48d228940/pgen.1007243.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/3140f9ff6183/pgen.1007243.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/594973095d61/pgen.1007243.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/791e9b1e56fb/pgen.1007243.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/9fc1b9b4acf4/pgen.1007243.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/cc3a6e882928/pgen.1007243.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/4678e40d4d6a/pgen.1007243.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/2955fe13199f/pgen.1007243.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/9a5f78b12694/pgen.1007243.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/69b44c095be0/pgen.1007243.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/d7f48d228940/pgen.1007243.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/3140f9ff6183/pgen.1007243.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53e1/5839592/594973095d61/pgen.1007243.g010.jpg

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