甲基化是控制基因表達(dá)的關(guān)鍵表觀遺傳學(xué)修飾,。加州大學(xué)Davis分校和加拿大英屬哥倫比亞大學(xué)的研究人員對(duì)胎盤(pán)進(jìn)行研究，揭示了人類(lèi)胎盤(pán)的甲基化組,，文章發(fā)表在本周的美國(guó)國(guó)家科學(xué)院院刊PNAS雜志上,。他們發(fā)現(xiàn)，37%的胎盤(pán)基因組具有低甲基化區(qū)域（部分甲基化區(qū)域PMD）,，這與大多數(shù)人體組織不同,，在大多數(shù)人體組織中70%的基因組都被高度甲基化。
基因組并非孤軍作戰(zhàn),，還有許多其他因素影響著基因的啟動(dòng)和關(guān)閉,，甲基化就是其中之一。這種表觀遺傳學(xué)修飾會(huì)通過(guò)給DNA添加甲基,，來(lái)調(diào)節(jié)基因的表達(dá),。這種機(jī)制對(duì)于人類(lèi)發(fā)育、癌癥和環(huán)境的生物學(xué)影響，都具有深遠(yuǎn)的意義,。
此前,，科學(xué)家們只在細(xì)胞系中發(fā)現(xiàn)過(guò)PMD，讓不少人懷疑它們是否真正存在于體內(nèi),。而這項(xiàng)研究首次在正常人體組織中發(fā)現(xiàn)了PMD,，證實(shí)它們存在于胎盤(pán)組織，是研究胎兒發(fā)育的重要窗口,。這不僅能增進(jìn)我們對(duì)表觀遺傳學(xué)的理解,，還可以為癌癥研究帶來(lái)啟示,，并且?guī)椭U明環(huán)境因素對(duì)胎兒發(fā)育的影響,。
“胎盤(pán)是母體和胎兒之間的重要紐帶，”文章資深作者,，醫(yī)學(xué)微生物學(xué)和免疫學(xué)教授Janine LaSalle說(shuō),。“在那里發(fā)生著許多重要的甲基化事件。”此外,，胎盤(pán)組織往往具有一些與癌癥相關(guān)的特性,。實(shí)際上，PMD就廣泛存在于許多癌癥（包括乳腺癌和結(jié)腸癌）中,。LaSalle認(rèn)為,，增進(jìn)對(duì)PMD的了解，將有助于開(kāi)發(fā)調(diào)節(jié)甲基化的抗癌藥物,。
這項(xiàng)研究還能增強(qiáng)人們檢測(cè)基因缺陷的能力,。甲基化和其他表觀遺傳學(xué)修飾，可以提供基因組以外的信息,，幫助科學(xué)家們確定特定DNA的來(lái)源,。“甲基化模式就像指紋，可以體現(xiàn)DNA源自什么組織,，而我們無(wú)法單從DNA序列得到這些信息,。”LaSalle說(shuō)。“甲基化研究可以為我們提供豐富的生物指標(biāo)資源,。”
研究人員利用MethylC-seq,、RNA-seq進(jìn)行了測(cè)序分析，并采用Illumina 450K Infinium甲基化芯片進(jìn)行檢測(cè),。研究顯示,，胎盤(pán)基因組中PMD占到37%，其中包括3,815個(gè)基因,，約為所有基因的17%,。PMD中的基因，翻譯成為蛋白的可能性較小。研究人員還發(fā)現(xiàn),，PMD也包含高度甲基化的CpG島（含有大量CG的基因組區(qū)域）,，而這往往與基因啟動(dòng)子的轉(zhuǎn)錄沉默有關(guān)。
研究人員指出,，胎盤(pán)PMD區(qū)域包含許多與神經(jīng)元發(fā)育有關(guān)的基因,，尤其是孤獨(dú)癥相關(guān)基因。他們認(rèn)為,，進(jìn)一步研究將會(huì)揭示表觀遺傳學(xué)對(duì)孤獨(dú)癥基因有怎樣的影響,。（生物谷Bioon.com）
doi:10.1073/pnas.1215145110
PMC:
PMID:
The human placenta methylome
Diane I. Schroedera,b,c,John D. Blaird,Paul Lottb,Hung On Ken Yub,Danna Honga,Florence Crarya,b,c,Paul Ashwooda,c,e,Cheryl Walkerc,f,Ian Korfb,Wendy P. Robinsond, and Janine M. LaSallea,b,c,1
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.
