Allele-Specific Methylome and Transcriptome Analysis Reveals Widespread Imprinting in the Human Placenta
Allele-Specific Methylome and Transcriptome Analysis Reveals Widespread Imprinting in the Human Placenta
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DOI：
10.1016/j.ajhg.2016.08.021
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发表时间：
2016-11-03
影响因子：
9.8
通讯作者：
Arima, Takahiro
中科院分区：
文献类型：
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作者：
Hamada, Hirotaka;Okae, Hiroaki;Arima, Takahiro
DNA甲基化在受精后被全局重编程，因此，除了在种系差异甲基化区域（gDMR）之外，亲本基因组在植入后具有相似的DNA甲基化谱。我们和其他人先前已经表明，人类囊胚可能含有数千个瞬时母体甲基化的gDMR（瞬时mDMR），其母体甲基化在植入后的胚胎组织中丢失。在这项研究中，我们对来自人类胎盘的纯化滋养层细胞进行了全基因组等位基因DNA甲基化分析，令人惊讶的是，发现超过四分之一的瞬时胚胎mDMR保持了其母系偏向的DNA甲基化。基于RNA测序的等位基因表达分析显示，一些胎盘特异性mDMR与印记基因的表达相关（例如，TIGAR、SLC 4A 7、PROSER 2-AS 1和KLHDC 10）和三个印迹基因簇。该方法还鉴定了一些X连锁gDMR。与其他哺乳动物的数据比较显示，胎盘中的基因组印记是高度可变的。这些发现突出了人类胎盘中生殖系DNA甲基化的不完全擦除;理解这种擦除对于理解正常胎盘发育和具有印记效应的发育障碍的发病机制非常重要。
DNA methylation is globally reprogrammed after fertilization, and as a result, the parental genomes have similar DNA-methylation profiles after implantation except at the germline differentially methylated regions (gDMRs). We and others have previously shown that human blastocysts might contain thousands of transient maternally methylated gDMRs (transient mDMRs), whose maternal methylation is lost in embryonic tissues after implantation. In this study, we performed genome-wide allelic DNA methylation analyses of purified trophoblast cells from human placentas and, surprisingly, found that more than one-quarter of the transient-in-embryo mDMRs maintained their maternally biased DNA methylation. RNA-sequencing-based allelic expression analyses revealed that some of the placenta-specific mDMRs were associated with expression of imprinted genes (e.g., TIGAR, SLC4A7, PROSER2-AS1, and KLHDC10), and three imprinted gene clusters were identified. This approach also identified some X-linked gDMRs. Comparisons of the data with those from other mammals revealed that genomic imprinting in the placenta is highly variable. These findings highlight the incomplete erasure of germline DNA methylation in the human placenta; understanding this erasure is important for understanding normal placental development and the pathogenesis of developmental disorders with imprinting effects.