文章基本信息

标题：Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction
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作者：Zhiyuan Chen ; Darren E. Hagen ; Christine G. Elsik 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：15
页码：4618-4623
DOI：10.1073/pnas.1422088112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceLarge offspring syndrome (LOS) is a fetal overgrowth condition that mimics the human syndrome Beckwith-Wiedemann. These conditions have been observed with higher incidence in offspring conceived with the use of assisted reproductive technologies and are believed to be the result of misregulation of a set of genes that are expressed only from the maternally or paternally inherited chromosomes. These genes are known as imprinted genes. In our study, we demonstrate that the kidney, brain, muscle, and liver of LOS fetuses show misregulation of multiple imprinted genes when compared with controls. Furthermore, we show that the magnitude of overgrowth in LOS fetuses correlates with the number of misregulated imprinted genes. Our results may help create diagnostics for these fetal syndromes. Embryos generated with the use of assisted reproductive technologies (ART) can develop overgrowth syndromes. In ruminants, the condition is referred to as large offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including overgrowth, enlarged tongue, and abdominal wall defects. These characteristics recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth syndrome Beckwith-Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus in LOS, the most common epimutation in BWS. Although the first case of ART-induced LOS was reported in 1995, studies have not yet determined the extent of LOI in this condition. Here, we determined allele-specific expression of imprinted genes previously identified in human and/or mouse in day [~]105 Bos taurus indicus x Bos taurus taurus F1 hybrid control and LOS fetuses using RNAseq. Our analysis allowed us to determine the monoallelic expression of 20 genes in tissues of control fetuses. LOS fetuses displayed variable LOI compared with controls. Biallelic expression of imprinted genes in LOS was associated with tissue-specific hypomethylation of the normally methylated parental allele. In addition, a positive correlation was observed between body weight and the number of biallelically expressed imprinted genes in LOS fetuses. Furthermore, not only was there loss of allele-specific expression of imprinted genes in LOS, but also differential transcript amounts of these genes between control and overgrown fetuses. In summary, we characterized previously unidentified imprinted genes in bovines and identified misregulation of imprinting at multiple loci in LOS. We concluded that LOS is a multilocus LOI syndrome, as is BWS.
关键词：genomic imprinting ; assisted reproductive technologies ; large offspring syndrome ; Beckwith–Wiedemann syndrome ; loss of imprinting