Stillbirth risk on <i>fat-1</i> transgenic foetus of sheep caused by deregulated DNA methylation of imprinted genes
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Imprinted genes play important roles on embryonic development. Aiming at the stillbirths in <i>fat-1</i> transgenic foetuses of sheep, we detected the DNA methylation levels of candidate CpG regions in five imprinted genes (<i>h19</i>, <i>igf2</i>, <i>igf2r</i>, <i>dlk1</i> and <i>gtl2</i>) of diverse tissues in the sheep foetuses, including both male and female <i>fat-1</i> transgenic stillbirths of sheep and the wild live-births of sheep. Imprinted gene <i>igf2</i>, <i>igf2r</i> and <i>dlk1</i> exhibited gender-neutral methylation except <i>h19</i>, which implies that the deregulated DNA methylation influenced by exogenous gene <i>fat-1</i> in imprinted gene <i>h19</i> more likely differs with gender. Besides, we found that exogenous gene <i>fat-1</i> could tend to influence DNA methylation of imprinted gene <i>igf2r</i> in kidney of sheep male-foetus by comparing number of differentially methylated CpG sites. Since the bio-function of <i>fat-1</i> on growth is consistent with <i>h19</i> and <i>igf2r</i>, but opposite with <i>igf2</i> and <i>dlk1</i>, we suggest that the stillbirth risk factors on sheep foetus with exogenous gene <i>fat-1</i> should be focused on abnormal development (of organs or cells) that probably caused by deregulated methylation status of imprinted genes, and the deregulated methylation may be driven by conflicting and overlapped bio-function between exogenous gene and imprinted genes, rather than extrinsic source of gene. <b>Abbreviations:</b> CSF: control sheep female-foetuses; CSM: control sheep male-foetuses; HTLA: Humane Treatment of Laboratory Animals; n-3 PUFA(s): omega-3 polyunsaturated fatty acid(s); TSF: <i>fat-1</i> transgenic sheep-stillbirths of female; TSM: <i>fat-1</i> transgenic sheep-stillbirths of male
印记基因（Imprinted genes）在胚胎发育过程中发挥关键作用。本研究针对绵羊fat-1转基因胎儿的死胎问题，检测了绵羊胎儿多种组织中5个印记基因（h19、igf2、igf2r、dlk1及gtl2）的候选CpG区域DNA甲基化水平，检测样本涵盖雌性与雄性fat-1转基因绵羊死胎，以及野生型足月存活绵羊胎儿。除h19外，igf2、igf2r与dlk1的甲基化水平无性别差异，这表明外源基因fat-1对印记基因h19造成的DNA甲基化失调可能存在性别特异性。此外，通过对比差异甲基化CpG位点的数量，我们发现外源基因fat-1更倾向于影响雄性绵羊胎儿肾脏中印记基因igf2r的DNA甲基化水平。鉴于fat-1在生长调控中的生物学功能与h19、igf2r一致，但与igf2、dlk1相反，本研究认为，携带外源基因fat-1的绵羊胎儿死胎风险因素应聚焦于由印记基因甲基化状态异常所引发的器官或细胞发育异常；而该甲基化失调可能由外源基因与印记基因之间的功能冲突与功能重叠所驱动，而非基因的外源来源本身。**缩写说明：** CSF：对照组雌性绵羊胎儿；CSM：对照组雄性绵羊胎儿；HTLA：实验动物人道处理准则；n-3 PUFA(s)：Omega-3多不饱和脂肪酸；TSF：雌性fat-1转基因绵羊死胎；TSM：雄性fat-1转基因绵羊死胎
