PNAS发布人类胎盘甲基化组

　　

生物通报道：甲基化是控制基因表达的关键表观遗传学修饰。加州大学Davis分校和加拿大英属哥伦比亚大学的研究人员对胎盘进行研究，揭示了人类胎盘的甲基化组，文章发表在本周的美国国家科学院院刊PNAS杂志上。他们发现，37%的胎盘基因组具有低甲基化区域（部分甲基化区域PMD），这与大多数人体组织不同，在大多数人体组织中70%的基因组都被高度甲基化。

基因组并非孤军作战，还有许多其他因素影响着基因的启动和关闭，甲基化就是其中之一。这种表观遗传学修饰会通过给DNA添加甲基，来调节基因的表达。这种机制对于人类发育、癌症和环境的生物学影响，都具有深远的意义。

此前，科学家们只在细胞系中发现过PMD，让不少人怀疑它们是否真正存在于体内。而这项研究首次在正常人体组织中发现了PMD，证实它们存在于胎盘组织，是研究胎儿发育的重要窗口。这不仅能增进我们对表观遗传学的理解，还可以为癌症研究带来启示，并且帮助阐明环境因素对胎儿发育的影响。

“胎盘是母体和胎儿之间的重要纽带，”文章资深作者，医学微生物学和免疫学教授Janine LaSalle说。“在那里发生着许多重要的甲基化事件。”此外，胎盘组织往往具有一些与癌症相关的特性。实际上，PMD就广泛存在于许多癌症（包括乳腺癌和结肠癌）中。LaSalle认为，增进对PMD的了解，将有助于开发调节甲基化的抗癌药物。

这项研究还能增强人们检测基因缺陷的能力。甲基化和其他表观遗传学修饰，可以提供基因组以外的信息，帮助科学家们确定特定DNA的来源。“甲基化模式就像指纹，可以体现DNA源自什么组织，而我们无法单从DNA序列得到这些信息。”LaSalle说。“甲基化研究可以为我们提供丰富的生物指标资源。”

研究人员利用MethylC-seq、RNA-seq进行了测序分析，并采用Illumina 450K Infinium甲基化芯片进行检测。研究显示，胎盘基因组中PMD占到37%，其中包括3,815个基因，约为所有基因的17%。PMD中的基因，翻译成为蛋白的可能性较小。研究人员还发现，PMD也包含高度甲基化的CpG岛（含有大量CG的基因组区域），而这往往与基因启动子的转录沉默有关。

研究人员指出，胎盘PMD区域包含许多与神经元发育有关的基因，尤其是孤独症相关基因。他们认为，进一步研究将会揭示表观遗传学对孤独症基因有怎样的影响。

 

（生物通编辑：叶予）

生物通推荐原文摘要：

The human placenta methylome

Tissue-specific DNA methylation is found at promoters, enhancers, and CpG islands but also over larger genomic regions. In most human tissues, the vast majority of the genome is highly methylated (>70%). Recently, sequencing of bisulfite-treated DNA (MethylC-seq) has revealed large partially methylated domains (PMDs) in some human cell lines. PMDs cover up to 40% of the genome and are associated with gene repression and inactive chromatin marks. However, to date, only cultured cells and cancers have shown evidence for PMDs. Here, we performed MethylC-seq in full-term human placenta and demonstrate it is the first known normal tissue showing clear evidence of PMDs. We found that PMDs cover 37% of the placental genome, are stable throughout gestation and between individuals, and can be observed with lower sensitivity in Illumina 450K Infinium data. RNA-seq analysis confirmed that genes in PMDs are repressed in placenta. Using a hidden Markov model to map placental PMDs genome-wide and compare them to PMDs in other cell lines, we found that genes within placental PMDs have tissue-specific functions. For regulatory regions, methylation levels in promoter CpG islands are actually higher for genes within placental PMDs, despite the lower overall methylation of surrounding regions. Similar to PMDs, polycomb-regulated regions are hypomethylated but smaller and distinct from PMDs, with some being hypermethylated in placenta compared with other tissues. These results suggest that PMDs are a developmentally dynamic feature of the methylome that are relevant for understanding both normal development and cancer and may be of use as epigenetic biomarkers.