Conserved role of intragenic DNA methylation in regulating alternative promoters.
Conserved role of intragenic DNA methylation in regulating alternative promoters.
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虽然5‘端启动子中DNA的甲基化抑制了基因的表达，但DNA甲基化在基因体中的作用尚不清楚。在哺乳动物中，组织和细胞类型特异的甲基化存在于一小部分5‘CpG岛(CGI)启动子中，而更大比例的甲基化发生在基因体上，与高度保守的序列相吻合。组织特异性的基因内甲基化可能会降低或矛盾地提高转录延伸效率。基因表达的封顶分析(CAGE)实验还表明，转录通常在基因内部和基因之间启动。为了研究基因内甲基化的作用，我们从人脑中生成了一张DNA甲基化图谱，涵盖了2800万个CpG位点中的2470万个。从CpG岛的高密度高分辨率覆盖中，发现大多数甲基化的CpG岛位于基因内和基因间区域，而5‘启动子中不到3%的CpG岛被甲基化。这三个位置的CpG岛都与转录起始的RNA标记重叠，未甲基化的CpG岛也与H3K4的三甲基化显著重叠，H3K4是一种富含在启动子上的组蛋白修饰。甲基化的一般模式和CpG岛特异性模式在小鼠组织中是保守的。对人类SHANK3基因及其小鼠同源物的深入研究表明，这种组织特异性DNA甲基化在体外和体内调节基因内启动子的活性。这些甲基化调节的选择性转录本以组织和细胞类型特定的方式表达，并在来自不同大脑区域的单一细胞类型中差异表达。这些结果支持基因内甲基化在调节基因体中的细胞上下文特定的替代启动子中的主要作用。
While the methylation of DNA in 5′ promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5′ CpG island (CGI) promoters, while a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were revealed to be in intragenic and intergenic regions, while less than 3% of CpG islands in 5′ promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
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