Inter- and intra-individual variation in allele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology.
Inter- and intra-individual variation in allele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology.
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DOI：
10.1371/journal.pgen.1001033
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发表时间：
2010-07-22
期刊：
影响因子：
4.5
通讯作者：
Sapienza C
中科院分区：
文献类型：
--
作者：
Turan N;Katari S;Gerson LF;Chalian R;Foster MW;Gaughan JP;Coutifaris C;Sapienza C
流行病学研究报道，在使用辅助生殖技术(ART)受孕的儿童中，涉及印记基因的罕见疾病的发生率较高，这表明ART程序可能会扰乱印记基因甲基化模式。我们在体外或体内受孕的儿童群体中检测了IGF2/H19和IGF2R基因座差异甲基化区域(DMRS)的个体内和个体间的DNA甲基化差异。我们发现这两个基因座的等位基因特异性甲基化在两组中都有很大的差异。母体IGF2/H19DMR的异常甲基化在体外培养组中更为常见，总体差异在体外培养组中也明显更大。我们根据IGF2/H19甲基化比率的二项分布的方差以及胎盘中X染色体失活分数的分布的近似来估计每组中的滋养层干细胞的数量。这两项独立的测量都表明，体外受孕组的胎盘来自的干细胞比体内受孕组的少。体外培养组胎盘组织中IGF2和H19mRNAs的表达均显著降低。尽管体外培养组的平均出生体重较低，但我们发现出生体重与IGF2或IGF2R转录水平以及IGF2/IGF2R转录水平的比率之间没有相关性。我们的结果表明，体外受孕与IGF2/H19基因座的异常甲基化模式有关。然而，与目前转录印记模型的预期相反，H19或IGF2 mRNA水平的个体间或个体内的差异可以用母体DMR DNA甲基化的差异来解释的很少。体外培养的胚胎的胚外组织似乎来自较少的滋养层干细胞。这种发育差异可能对胎盘和胎儿的生长有影响。我们已经对体外受孕的儿童群体进行了筛查，以检测携带父母来源特异性甲基化标记的两个基因座的表观遗传学变化。我们观察到，在两组胚胎外组织中，表观遗传变异性都大于胚胎组织，这一点在小鼠身上也得到了证实。体外培养组胚胎外组织的个体内变异水平较高，似乎是因为这些胚胎的滋养层干细胞较少。我们还出人意料地观察到，亲本来源相关的表观遗传标记的可变性与基因表达的相关性很差。事实上，IGF2转录水平的个体间差异水平如此之高，以至于适当的转录印迹与完全丧失印迹相比IGF2mRNA的推测减少了一半，将不到总群体差异的5%。考虑到印记基因表达的这种水平的可变性，应该重新考虑“父母冲突”作为选择性力量在人类IGF2/H19基因座维持印记基因表达的假定操作。
Epidemiological studies have reported a higher incidence of rare disorders involving imprinted genes among children conceived using assisted reproductive technology (ART), suggesting that ART procedures may be disruptive to imprinted gene methylation patterns. We examined intra- and inter-individual variation in DNA methylation at the differentially methylated regions (DMRs) of the IGF2/H19 and IGF2R loci in a population of children conceived in vitro or in vivo. We found substantial variation in allele-specific methylation at both loci in both groups. Aberrant methylation of the maternal IGF2/H19 DMR was more common in the in vitro group, and the overall variance was also significantly greater in the in vitro group. We estimated the number of trophoblast stem cells in each group based on approximation of the variance of the binomial distribution of IGF2/H19 methylation ratios, as well as the distribution of X chromosome inactivation scores in placenta. Both of these independent measures indicated that placentas of the in vitro group were derived from fewer stem cells than the in vivo conceived group. Both IGF2 and H19 mRNAs were significantly lower in placenta from the in vitro group. Although average birth weight was lower in the in vitro group, we found no correlation between birth weight and IGF2 or IGF2R transcript levels or the ratio of IGF2/IGF2R transcript levels. Our results show that in vitro conception is associated with aberrant methylation patterns at the IGF2/H19 locus. However, very little of the inter- or intra-individual variation in H19 or IGF2 mRNA levels can be explained by differences in maternal DMR DNA methylation, in contrast to the expectations of current transcriptional imprinting models. Extraembryonic tissues of embryos cultured in vitro appear to be derived from fewer trophoblast stem cells. It is possible that this developmental difference has an effect on placental and fetal growth. We have screened a population of children conceived in vitro for epigenetic alterations at two loci that carry parent-of-origin specific methylation marks. We made the observation that epigenetic variability was greater in extraembryonic tissues than embryonic tissues in both groups, as has also been demonstrated in the mouse. The greater level of intra-individual variation in extraembryonic tissues of the in vitro group appears to result from these embryos having fewer trophoblast stem cells. We also made the unexpected observation that variability in parental origin-dependent epigenetic marking was poorly correlated with gene expression. In fact, there is such a high level of inter-individual variation in IGF2 transcript level that the presumed half-fold reduction in IGF2 mRNA accounted for by proper transcriptional imprinting versus complete loss of imprinting would account for less than 5% of the total population variance. Given this level of variability in the expression of an imprinted gene, the presumed operation of “parental conflict” as the selective force acting to maintain imprinted gene expression at the IGF2/H19 locus in the human should be revisited.
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影响因子：
30.8
作者：
KALSCHEUER, VM;MARIMAN, EC;ROPERS, HH
通讯作者：
ROPERS, HH
影响因子：
64.8
作者：
Hark, AT;Schoenherr, CJ;Tilghman, SM
通讯作者：
Tilghman, SM
DOI：
10.1073/pnas.0906183107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Feinberg, Andrew P.;Irizarry, Rafael A.
通讯作者：
Irizarry, Rafael A.
DOI：
10.1073/pnas.0308560101
发表时间：
2004-04-20
影响因子：
11.1
作者：
Fernández-Gonzalez, R;Moreira, P;Gutiérrez-Adán, A
通讯作者：
Gutiérrez-Adán, A
影响因子：
11.4
作者：
de Villena, FPM;de la Casa-Esperón, E;Sapienza, C
通讯作者：
Sapienza, C