The human placenta methylome
The human placenta methylome
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DOI：
10.1073/pnas.1215145110
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发表时间：
2013-04-09
影响因子：
11.1
通讯作者：
LaSalle, Janine M.
中科院分区：
文献类型：
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作者：
Schroeder, Diane I.;Blair, John D.;LaSalle, Janine M.
组织特异性DNA甲基化存在于启动子、增强子和CpG岛，但也存在于更大的基因组区域。在大多数人类组织中，绝大多数基因组是高度甲基化的（>70%）。最近，亚硫酸氢盐处理的DNA（MethylC-seq）的测序已经在一些人类细胞系中揭示了大的部分甲基化结构域（PMD）。PMD覆盖高达40%的基因组，并与基因抑制和非活性染色质标记相关。然而，迄今为止，只有培养的细胞和癌症显示出PMD的证据。在这里，我们在足月人类胎盘中进行了MethylC-seq，并证明它是第一个已知的正常组织，显示出PMD的明确证据。我们发现PMD覆盖胎盘基因组的37%，在整个妊娠期和个体之间稳定，并且可以在Illumina 450 K Infinium数据中以较低的灵敏度观察到。RNA-seq分析证实PMD中的基因在胎盘中受到抑制。使用隐马尔可夫模型来映射胎盘PMD全基因组，并将其与其他细胞系中的PMD进行比较，我们发现胎盘PMD内的基因具有组织特异性功能。对于调节区域，启动子CpG岛的甲基化水平实际上对于胎盘PMD内的基因更高，尽管周围区域的总体甲基化水平较低。与PMD类似，多梳调控区是低甲基化的，但更小，与PMD不同，与其他组织相比，胎盘中的一些是高甲基化的。这些结果表明，PMD是甲基化组的发育动态特征，其与理解正常发育和癌症相关，并且可以用作表观遗传生物标志物。
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.