Passive and active DNA methylation and the interplay with genetic variation in gene regulation.
Passive and active DNA methylation and the interplay with genetic variation in gene regulation.
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DOI：
10.7554/elife.00523
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发表时间：
2013-06-04
期刊：
影响因子：
7.7
通讯作者：
Dermitzakis ET
中科院分区：
文献类型：
--
作者：
Gutierrez-Arcelus M;Lappalainen T;Montgomery SB;Buil A;Ongen H;Yurovsky A;Bryois J;Giger T;Romano L;Planchon A;Falconnet E;Bielser D;Gagnebin M;Padioleau I;Borel C;Letourneau A;Makrythanasis P;Guipponi M;Gehrig C;Antonarakis SE;Dermitzakis ET
DNA甲基化是一种重要的表观遗传标记，其在基因调控中的作用及其对基因组序列和环境的依赖性尚不完全清楚。在这项研究中，我们对GenCord人群队列中三种不同细胞类型的遗传变异，DNA甲基化和转录组测序数据之间的机制关系提供了新的见解。我们发现，个体之间DNA甲基化和基因表达变异之间的关联可能是由于与分化过程中建立甲基化表达模式的机制不同。此外，细胞类型的差异DNA甲基化可能描绘了一个平台，其中局部个体间的变化可能会响应或作用于基因调控。我们发现，与遗传调控变异不同，单独的DNA甲基化并不能显著驱动等位基因特异性表达。最后，使用遗传变异以及与TF丰度的相关性推断的机制关系揭示了DNA甲基化对影响基因表达的调控相互作用的被动和主动作用。DOI：www.example.com变异发生在我们的基因组中。这些变异可以导致基因在个体之间以略微不同的方式表达（打开）。此外，同一基因也可以在个体内的不同细胞中以不同的方式表达。第三个层次的变异是由表观遗传标记提供的：这些分子在特定的点上与DNA结合，并对附近基因的表达产生深远的影响。一个这样的表观遗传标记是在胞嘧啶碱基上添加甲基，这一过程被称为DNA甲基化。DNA甲基化通常发生在胞嘧啶碱基与鸟嘌呤碱基相邻时，形成CpG位点。在哺乳动物中，大多数CpG位点都连接有甲基，尽管具有大量CpG位点的区域（称为CpG岛）大多未甲基化。最初的研究表明，甲基化阻止了特定基因的表达，但最近的研究表明，甲基化可能与基因表达的减少和增加有关。此外，尚不清楚该关联是否活跃（即，甲基化的变化驱动基因表达的变化）或被动（DNA甲基化是基因调控的结果）。现在，Gutierrez-Arcelus等人进行了一项大规模的研究，以澄清个体之间三种不同类型的基因相关变异之间的关系。他们从204名婴儿的脐带中提取了成纤维细胞、T细胞和淋巴母细胞，并分析了它们的DNA序列、基因表达和DNA甲基化的变化。他们的研究结果表明，这三者之间的联系比以前认为的要复杂得多。Gutierrez-Arcelus等人表明，控制个体中DNA甲基化和基因表达变化之间关联的机制可能与细胞分化过程中负责建立甲基化模式的机制不同。他们还发现DNA甲基化和基因表达之间的关联可以是主动的或被动的，并且可以取决于它们在我们基因组中发生的背景。最后，当基因的两个拷贝或等位基因在给定细胞中不相等地表达时，表达的差异主要由DNA序列变异调节，DNA甲基化本身几乎没有作用。同样复杂的相互作用和影响，预计在遗传和表观遗传变异的进一步研究。DOI：www.example.com网站
DNA methylation is an essential epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment are not fully understood. In this study we provide novel insights into the mechanistic relationships between genetic variation, DNA methylation and transcriptome sequencing data in three different cell-types of the GenCord human population cohort. We find that the association between DNA methylation and gene expression variation among individuals are likely due to different mechanisms from those establishing methylation-expression patterns during differentiation. Furthermore, cell-type differential DNA methylation may delineate a platform in which local inter-individual changes may respond to or act in gene regulation. We show that unlike genetic regulatory variation, DNA methylation alone does not significantly drive allele specific expression. Finally, inferred mechanistic relationships using genetic variation as well as correlations with TF abundance reveal both a passive and active role of DNA methylation to regulatory interactions influencing gene expression. DOI: http://dx.doi.org/10.7554/eLife.00523.001 Variations occur throughout our genome. These variations can cause genes to be expressed (switched on) in slightly different ways among individuals. Moreover, the same gene can also be expressed in different ways in different cells within an individual. A third level of variation is supplied by epigenetic markers: these are molecules that bind to the DNA at specific points and can have profound effects on the expression of nearby genes. One such epigenetic marker is the addition of a methyl group to a cytosine base, a process that is known as DNA methylation. DNA methylation usually happens when a cytosine base is next to a guanine base, forming a CpG site. In mammals, most CpG sites have methyl groups attached, although regions with a lot of CpG sites (called CpG islands) are mostly unmethylated. Initial studies suggested that methylation prevented particular genes from being expressed, but more recent work has indicated that methylation can be associated with both reduced and increased expression of genes. Moreover, it is not clear if this association is active (i.e., changes in methylation drive changes in gene expression) or passive (DNA methylation is the result of gene regulation). Now, Gutierrez-Arcelus et al. have carried out a large-scale study to clarify the relationships between three different types of gene-related variations among individuals. They extracted fibroblasts, T-cells and lymphoblastoid cells from the umbilical cords of 204 babies, and analysed them for variations in DNA sequence, gene expression and DNA methylation. Their results show that the associations between the three are more complex than was previously thought. Gutierrez-Arcelus et al. show that the mechanisms that control the association between the variations in DNA methylation and gene expression in individuals are likely to be different to those that are responsible for the establishment of methylation patterns during the process of cell differentiation. They also find that the association between DNA methylation and gene expression can be either active or passive, and can depend on the context in which they occur in our genome. Finally, where the two copies or alleles of a gene are not equally expressed in a given cell, the difference in expression is primarily regulated by DNA sequence variation, with DNA methylation having little or no role on its own. Equally complex interactions and effects are expected in further studies of genetic and epigenetic variation. DOI: http://dx.doi.org/10.7554/eLife.00523.002