Consistent inverse correlation between DNA methylation of the first intron and gene expression across tissues and species.
Consistent inverse correlation between DNA methylation of the first intron and gene expression across tissues and species.
复制标题
DOI：
10.1186/s13072-018-0205-1
复制
发表时间：
2018-06-29
影响因子：
3.9
通讯作者：
Piferrer F
中科院分区：
文献类型：
--
作者：
Anastasiadi D;Esteve-Codina A;Piferrer F
DNA甲基化是真核生物基因表达调控的主要表观遗传机制之一。在标准模型中，基因启动子中的甲基化受到了最多的关注，因为它通常与转录沉默有关。然而，最近在人类组织中的研究表明，转录起始点下游区域的甲基化对基因表达具有很高的信息量。此外，在一些细胞类型和特定基因中，已经发现第一内含子的甲基化与基因表达有关。第一内含子是一种典型的富含增强子的基因特征。然而，对脊椎动物第一内含子DNA甲基化与基因表达之间的关系进行全基因组、组织独立的系统比较分析还没有被探索过。本研究最重要的发现是：(1)利用现代鱼类的不同组织，我们显示了基因组范围内第一内含子的DNA甲基化与基因表达之间明显的、组织独立的准线性负相关关系。(2)这种关系在脊椎动物中是保守的，因为它也存在于模型河豚、模型青蛙和不同人类组织的基因组中。在所查询的基因特征、组织和物种中，第一内含子与基因表达的负相关最为一致。(3)与其他基因特征相比，我们在第一内含子中发现了更多的组织特异性差异甲基化区域(TDMRS)。这些tDMR与基因表达呈正相关或负相关，表明了不同的组织特异性调控机制。(4)最后，我们在转录因子结合基序中发现了CPGS，这些基序富含在第一内含子中，其甲基化倾向于随着距离第一外显子-第一内含子边界的距离而增加，伴随着基因表达的降低。我们的综合分析清楚地揭示了第一内含子甲基化水平的重要和保守的作用，以及它与基因表达的反向关联，而与组织和物种无关。这些发现不仅有助于我们对基因表达的表观遗传调控的基本理解，而且还将第一内含子确定为关于DNA甲基化与基因表达之间关系的信息基因特征，这是未来研究的重点。本文的在线版本(10.1186/s13072-0180205-1)包含补充材料，可供授权用户使用。
DNA methylation is one of the main epigenetic mechanisms for the regulation of gene expression in eukaryotes. In the standard model, methylation in gene promoters has received the most attention since it is generally associated with transcriptional silencing. Nevertheless, recent studies in human tissues reveal that methylation of the region downstream of the transcription start site is highly informative of gene expression. Also, in some cell types and specific genes it has been found that methylation of the first intron, a gene feature typically rich in enhancers, is linked with gene expression. However, a genome-wide, tissue-independent, systematic comparative analysis of the relationship between DNA methylation in the first intron and gene expression across vertebrates has not been explored yet. The most important findings of this study are: (1) using different tissues from a modern fish, we show a clear genome-wide, tissue-independent quasi-linear inverse relationship between DNA methylation of the first intron and gene expression. (2) This relationship is conserved across vertebrates, since it is also present in the genomes of a model pufferfish, a model frog and different human tissues. Among the gene features, tissues and species interrogated, the first intron’s negative correlation with the gene expression was most consistent. (3) We identified more tissue-specific differentially methylated regions (tDMRs) in the first intron than in any other gene feature. These tDMRs have positive or negative correlation with gene expression, indicative of distinct mechanisms of tissue-specific regulation. (4) Lastly, we identified CpGs in transcription factor binding motifs, enriched in the first intron, the methylation of which tended to increase with the distance from the first exon–first intron boundary, with a concomitant decrease in gene expression. Our integrative analysis clearly reveals the important and conserved role of the methylation level of the first intron and its inverse association with gene expression regardless of tissue and species. These findings not only contribute to our basic understanding of the epigenetic regulation of gene expression but also identify the first intron as an informative gene feature regarding the relationship between DNA methylation and gene expression where future studies should be focused. The online version of this article (10.1186/s13072-018-0205-1) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
2.6
作者：
Chen, Xiaowu;Wang, Zhipeng;Zhao, Jinliang
通讯作者：
Zhao, Jinliang
影响因子：
4.5
作者：
Hernando-Herraez I;Prado-Martinez J;Garg P;Fernandez-Callejo M;Heyn H;Hvilsom C;Navarro A;Esteller M;Sharp AJ;Marques-Bonet T
通讯作者：
Marques-Bonet T
影响因子：
4.6
作者：
Cao J;Wei C;Liu D;Wang H;Wu M;Xie Z;Capellini TD;Zhang L;Zhao F;Li L;Zhong T;Wang L;Lu J;Liu R;Zhang S;Du Y;Zhang H;Du L
通讯作者：
Du L
影响因子：
46.9
作者：
Ball, Madeleine P.;Li, Jin Billy;Gao, Yuan;Lee, Je-Hyuk;LeProust, Emily M.;Park, In-Hyun;Xie, Bin;Daley, George Q.;Church, George M.
通讯作者：
Church, George M.
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J