Tissue-specific effects of genetic and epigenetic variation on gene regulation and splicing.
Tissue-specific effects of genetic and epigenetic variation on gene regulation and splicing.
复制标题
遗传和表观遗传变异对基因调节和剪接的组织特异性作用。
DOI：
10.1371/journal.pgen.1004958
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发表时间：
2015-01
期刊：
影响因子：
4.5
通讯作者：
Dermitzakis ET
中科院分区：
文献类型：
--
作者：
Gutierrez-Arcelus M;Ongen H;Lappalainen T;Montgomery SB;Buil A;Yurovsky A;Bryois J;Padioleau I;Romano L;Planchon A;Falconnet E;Bielser D;Gagnebin M;Giger T;Borel C;Letourneau A;Makrythanasis P;Guipponi M;Gehrig C;Antonarakis SE;Dermitzakis ET
了解遗传变异如何影响不同的细胞表型，如基因表达水平，选择性剪接和DNA甲基化水平，对于更好地理解复杂的疾病和性状至关重要。此外，DNA甲基化的个体间变异如何与基因表达相关的研究才刚刚开始。在这项研究中，我们使用了204个新生欧洲人的淋巴母细胞系，T细胞和脐带来源的成纤维细胞的GenCord队列。这些样本先前已对250万个SNP进行了基因分型，进行了mRNA测序，并测定了482，421个CpG位点的甲基化水平。我们观察到与表达水平相关的甲基化位点在增强子、基因体和CpG岛岸中富集。我们发现，虽然DNA甲基化和基因表达之间的相关性可以是正的或负的，但在不同的细胞类型中是非常一致的。然而，这种与基因表达的表观遗传关联似乎比对基因表达或DNA甲基化的遗传效应更具组织特异性（在基于P值和细胞类型之间的效应大小相关性的共享估计中观察到）。这种遗传效应的优势也可以通过个体之间等位基因特异性表达差异主导组织特异性效应的观察来反映。此外，我们发现了对选择性剪接的遗传效应，有趣的是，大量的DNA甲基化与选择性剪接相关，两者都是以组织特异性的方式。参与这些关联的SNP和甲基化位点的位置突出了启动子近端和远端调控区对选择性剪接的参与。总的来说，我们的研究结果提供了高分辨率的分析，显示基因组序列变异如何对不同细胞类型的细胞表型产生广泛的影响，而表观遗传因素提供了更具组织特异性的第二层变异。此外，这种组织特异性如何在分子性状的相互关系中变化，以及这些发生的细节，可以对基因调控和细胞生物学作为一个整体产生进一步的见解。为了更好地了解个体之间的遗传差异如何导致疾病，了解遗传变异如何影响组成人体的不同组织中的细胞功能至关重要。从195名新生儿的脐带中，我们先前获得了三种不同的细胞类型：成纤维细胞，T细胞和永生化B细胞。从每种细胞类型的每个个体中，我们测量了基因组的四个特征：1）遗传差异，2）DNA甲基化，DNA的表观遗传修饰可以影响其功能状态，3）基因表达-基因活性的量，4）选择性剪接-基因的不同版本表现出来。我们发现DNA序列的数千种遗传变异影响甲基化，基因表达和剪接。我们表明，虽然这些遗传效应通常会影响多种细胞类型，但这些效应的强度在细胞类型之间存在差异。DNA的表观遗传甲基化标记也与基因表达相关，特别是通常与剪接相关。由于基因表达、DNA甲基化和可变剪接的异常与疾病有关，因此继续研究这些性状如何相互关联并受细胞类型遗传变异的影响是很重要的。
Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. In this study, we use the GenCord cohort of 204 newborn Europeans’ lymphoblastoid cell lines, T-cells and fibroblasts derived from umbilical cords. The samples were previously genotyped for 2.5 million SNPs, mRNA-sequenced, and assayed for methylation levels in 482,421 CpG sites. We observe that methylation sites associated to expression levels are enriched in enhancers, gene bodies and CpG island shores. We show that while the correlation between DNA methylation and gene expression can be positive or negative, it is very consistent across cell-types. However, this epigenetic association to gene expression appears more tissue-specific than the genetic effects on gene expression or DNA methylation (observed in both sharing estimations based on P-values and effect size correlations between cell-types). This predominance of genetic effects can also be reflected by the observation that allele specific expression differences between individuals dominate over tissue-specific effects. Additionally, we discover genetic effects on alternative splicing and interestingly, a large amount of DNA methylation correlating to alternative splicing, both in a tissue-specific manner. The locations of the SNPs and methylation sites involved in these associations highlight the participation of promoter proximal and distant regulatory regions on alternative splicing. Overall, our results provide high-resolution analyses showing how genome sequence variation has a broad effect on cellular phenotypes across cell-types, whereas epigenetic factors provide a secondary layer of variation that is more tissue-specific. Furthermore, the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole. In order to better understand how genetic differences between individuals can cause diseases, it is crucial to understand how genetic variants affect cellular functions in the different tissues that compose the human body. From the umbilical cord of 195 newborn babies, we previously obtained three different cell-types: fibroblasts, T-cells and immortalized B-cells. From every individual in each cell type we measured four features across the genome: 1) genetic differences, 2) DNA methylation, an epigenetic modification of DNA that can affect its functional state, 3) gene expression—the amount of gene activity, 4) alternative splicing—which of the different versions of a gene is manifested. We find thousands of genetic variants of the DNA sequence that affect methylation, gene expression, and splicing. We show that while these genetic effects often affect multiple cell-types, the strength of these effects varies between cell-types. Also epigenetic methylation marks of DNA associate to gene expression and particularly often to splicing. Since abnormalities in gene expression, DNA methylation and alternative splicing are associated to diseases, it is important to continue studying how these traits are inter-related and affected by genetic variation across cell-types.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
剪接的组织特异性遗传控制：对复杂性状的研究的影响。
影响因子：
9.8
作者：
Heinzen EL;Ge D;Cronin KD;Maia JM;Shianna KV;Gabriel WN;Welsh-Bohmer KA;Hulette CM;Denny TN;Goldstein DB
通讯作者：
Goldstein DB
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.7
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
通讯作者：
Dermitzakis ET
影响因子：
4.5
作者：
Coulombe-Huntington J;Lam KC;Dias C;Majewski J
通讯作者：
Majewski J