Global misregulation of genes largely uncoupled to DNA methylome epimutations characterizes a congenital overgrowth syndrome

Zhiyuan Chen,Christine G Elsik,Tieming Ji,Rocío M Rivera,Darren E Hagen

doi:10.1038/s41598-017-13012-z

Zhiyuan Chen, Christine G Elsik + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-13012-z

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Abstract

Assisted reproductive therapies (ART) have become increasingly common worldwide and numerous retrospective studies have indicated that ART-conceived children are more likely to develop the overgrowth syndrome Beckwith-Wiedemann (BWS). In bovine, the use of ART can induce a similar overgrowth condition, which is referred to as large offspring syndrome (LOS). Both BWS and LOS involve misregulation of imprinted genes. However, it remains unknown whether molecular alterations at non-imprinted loci contribute to these syndromes. Here we examined the transcriptome of skeletal muscle, liver, kidney, and brain of control and LOS bovine fetuses and found that different tissues within LOS fetuses have perturbations of distinct gene pathways. Notably, in skeletal muscle, multiple pathways involved in myoblast proliferation and fusion into myotubes are misregulated in LOS fetuses. Further, characterization of the DNA methylome of skeletal muscle demonstrates numerous local methylation differences between LOS and controls; however, only a small percent of differentially expressed genes (DEGs), including the imprinted gene IGF2R, could be associated with the neighboring differentially methylated regions. In summary, we not only show that misregulation of non-imprinted genes and loss-of-imprinting characterize the ART-induced overgrowth syndrome but also demonstrate that most of the DEGs is not directly associated with DNA methylome epimutations.

Highlights

The use of Assisted reproductive therapies (ART) has become increasingly common worldwide and each year approximately six percent of infants born in developed countries are conceived employing these technologies[1]
It is well accepted that loss-of-imprinting can contribute to these overgrowth syndromes, and as such have been coined “loss-of-imprinting syndromes”, it remains unknown whether aberrant gene expression and DNA methylation occur at non-imprinted loci and to what extent these molecular alterations contribute to the variable phenotypes observed in these conditions
In order to determine to what extent the transcriptome is altered in bovine large offspring syndrome (LOS) fetuses, we analyzed RNA sequencing (RNAseq) data of skeletal muscle, liver, kidney, and brain from four control and four LOS day ~105 (d104–106) B. t. indicus × B. t. taurus F1 fetuses that we generated in a previous study[18] (Supplementary Table 1)

Summary

Introduction

The use of ART has become increasingly common worldwide and each year approximately six percent of infants born in developed countries are conceived employing these technologies[1]. It is well accepted that loss-of-imprinting can contribute to these overgrowth syndromes, and as such have been coined “loss-of-imprinting syndromes”, it remains unknown whether aberrant gene expression and DNA methylation occur at non-imprinted loci and to what extent these molecular alterations contribute to the variable phenotypes observed in these conditions. To address this question, we examined the transcriptome of skeletal muscle, liver, kidney, and brain of four control and four LOS day ~105 Bos taurus indicus The observation that most identified DMRs could not be directly associated with aberrant gene expression suggests that caution should be exercised when making conclusions about the etiology of such syndromes by interpreting time-point-specific DNA methylation data

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Conclusion