DNA Methylation Landscapes of Human Fetal Development.
DNA Methylation Landscapes of Human Fetal Development.
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DOI：
10.1371/journal.pgen.1005583
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发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Chuva de Sousa Lopes SM
中科院分区：
文献类型：
--
作者：
Slieker RC;Roost MS;van Iperen L;Suchiman HE;Tobi EW;Carlotti F;de Koning EJ;Slagboom PE;Heijmans BT;Chuva de Sousa Lopes SM
甲基组的重塑是哺乳动物发育和细胞分化的标志。然而，目前关于人体组织规格和器官发育中的DNA甲基化动力学的知识主要来自体外和动物模型研究的推断。在这里，我们报告了在妊娠前三个月和妊娠中期（9,18和22周）使用四种人体组织（羊膜，肌肉，肾上腺和胰腺）的450k阵列的DNA甲基化图景。我们发现，由组织特异性低甲基化CpG位点构成的组织特异性特征，在妊娠9周（W9）就已经存在。此外，我们报道了从W9到W22的DNA甲基化的大规模重构。DNA甲基化的增加优先发生在涉及一般发育过程的基因附近，而DNA甲基化的损失则指向具有组织特异性功能的基因。动态DNA甲基化与增强子相关，而与启动子无关。将我们的数据与胎儿外部肾上腺、大脑和肝脏的数据进行比较，揭示了胎儿发育过程中DNA甲基化轨迹的惊人相似性。基因表达数据分析表明，动态DNA甲基化与发育程序的渐进式抑制和参与组织特异性过程的基因的激活有关。人类胎儿发育的DNA甲基化景观提供了对指导组织规范和导致器官功能的调节元件的见解。DNA甲基化是一个关键的表观遗传标记。成人组织具有高度不同的全基因组DNA甲基化特征。这些特征在人类胎儿发育过程中是如何产生的，在很大程度上是未知的。在这里，我们研究了四种组织（羊膜、肌肉、肾上腺、胰腺）在人类胎儿发育的前三个月和中期的DNA甲基化谱。早在怀孕的前三个月，就在每个组织中发现了一个组织特异性的特征。然而，在妊娠早期和中期，发现大量的基因组区域获得或失去DNA甲基化。获得甲基化的基因组区域与发育过程的关闭有关，而失去甲基化的基因组区域与组织特异性功能的激活有关。这些关于人类胎儿发育的DNA甲基化景观的发现是重要的，因为它们提供了对指导组织规范和导致器官功能的调节元件的见解。
Remodelling the methylome is a hallmark of mammalian development and cell differentiation. However, current knowledge of DNA methylation dynamics in human tissue specification and organ development largely stems from the extrapolation of studies in vitro and animal models. Here, we report on the DNA methylation landscape using the 450k array of four human tissues (amnion, muscle, adrenal and pancreas) during the first and second trimester of gestation (9,18 and 22 weeks). We show that a tissue-specific signature, constituted by tissue-specific hypomethylated CpG sites, was already present at 9 weeks of gestation (W9). Furthermore, we report large-scale remodelling of DNA methylation from W9 to W22. Gain of DNA methylation preferentially occurred near genes involved in general developmental processes, whereas loss of DNA methylation mapped to genes with tissue-specific functions. Dynamic DNA methylation was associated with enhancers, but not promoters. Comparison of our data with external fetal adrenal, brain and liver revealed striking similarities in the trajectory of DNA methylation during fetal development. The analysis of gene expression data indicated that dynamic DNA methylation was associated with the progressive repression of developmental programs and the activation of genes involved in tissue-specific processes. The DNA methylation landscape of human fetal development provides insight into regulatory elements that guide tissue specification and lead to organ functionality. Methylation of DNA is a key epigenetic mark. Adult tissues have highly distinct genome-wide DNA methylation signatures. How these signatures arise during human fetal development is largely unknown. Here, we studied DNA methylation profiles of four tissues (amnion, muscle, adrenal, pancreas) during first and second trimester of human fetal development. Already in the first trimester, a tissue-specific signature was found in each of the tissues. However, during the first and second trimester, a substantial number of genomic regions were found to gain and lose DNA methylation. Genomic regions that gained methylation were associated with the shut-down of developmental processes, while genomic regions that lose methylation were associated with the activation of tissue-specific functions. These findings on the DNA methylation landscape of human fetal development are important as they provide insight into regulatory elements that guide tissue specification and lead to organ functionality.