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Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction.

ABSTRACT: 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 × 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.

SUBMITTER: Chen Z

PROVIDER: S-EPMC4403167 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction.

Chen Zhiyuan Z Hagen Darren E DE Elsik Christine G CG Ji Tieming T Morris Collin James CJ Moon Laura Emily LE Rivera Rocío Melissa RM

Proceedings of the National Academy of Sciences of the United States of America 20150330 15

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 com ...[more]

PMID: 25825726

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Project description:Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance. Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5′ tRFs in muscle and 5′ halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6). Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.

Project description:Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance. Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5' tRFs in muscle and 5' halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6). Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.

Project description:Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from Eed-null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen enriched cell population and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter Slc38a4 was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of Eed in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting.

Dataset Information

Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction.

Publications

Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction.

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