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首页> 外文期刊>Molecular and Cellular Biology >Developmentally Programmed 3′ CpG Island Methylation Confers Tissue- and Cell-Type-Specific Transcriptional Activation
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Developmentally Programmed 3′ CpG Island Methylation Confers Tissue- and Cell-Type-Specific Transcriptional Activation

机译：开发编程的3'CpG岛甲基化赋予组织和细胞类型特定的转录激活。

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During development, a small but significant number of CpG islands (CGIs) become methylated. The timing of developmentally programmed CGI methylation and associated mechanisms of transcriptional regulation during cellular differentiation, however, remain poorly characterized. Here, we used genome-wide DNA methylation microarrays to identify epigenetic changes during human embryonic stem cell (hESC) differentiation. We discovered a group of CGIs associated with developmental genes that gain methylation after hESCs differentiate. Conversely, erasure of methylation was observed at the identified CGIs during subsequent reprogramming to induced pluripotent stem cells (iPSCs), further supporting a functional role for the CGI methylation. Both global gene expression profiling and quantitative reverse transcription-PCR (RT-PCR) validation indicated opposing effects of CGI methylation in transcriptional regulation during differentiation, with promoter CGI methylation repressing and 3′ CGI methylation activating transcription. By studying diverse human tissues and mouse models, we further confirmed that developmentally programmed 3′ CGI methylation confers tissue- and cell-type-specific gene activation in vivo. Importantly, luciferase reporter assays provided evidence that 3′ CGI methylation regulates transcriptional activation via a CTCF-dependent enhancer-blocking mechanism. These findings expand the classic view of mammalian CGI methylation as a mechanism for transcriptional silencing and indicate a functional role for 3′ CGI methylation in developmental gene regulation.
机译：在开发过程中，少量但大量的CpG岛（CGI）被甲基化。然而，在细胞分化过程中，发育程序化的CGI甲基化的时机和相关的转录调控机制仍然不明确。在这里，我们使用了全基因组DNA甲基化微阵列来鉴定人类胚胎干细胞（hESC）分化过程中的表观遗传学变化。我们发现了一组与hESCs分化后获得甲基化的发育基因相关的CGI。相反，在随后重编程为诱导性多能干细胞（iPSC）的过程中，在已鉴定的CGI处观察到甲基化消失，进一步支持了CGI甲基化的功能性作用。总体基因表达谱和定量逆转录-PCR（RT-PCR）验证均表明CGI甲基化在分化期间的转录调控中具有相反的作用，其中启动子CGI甲基化抑制和3'CGI甲基化激活转录。通过研究各种人体组织和小鼠模型，我们进一步证实了发育程序化的3'CGI甲基化赋予了组织和细胞类型特异性的体内基因激活。重要的是，萤光素酶报告基因检测提供了3'CGI甲基化通过CTCF依赖性增强子阻断机制调节转录激活的证据。这些发现扩展了哺乳动物CGI甲基化作为转录沉默机制的经典观点，并表明了3'CGI甲基化在发育基因调控中的功能性作用。

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