Genetic and epigenetic regulation of gene expression in fetal and adult human livers.
Genetic and epigenetic regulation of gene expression in fetal and adult human livers.
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DOI：
10.1186/1471-2164-15-860
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发表时间：
2014-10-04
期刊：
影响因子：
4.4
通讯作者：
Milani L
中科院分区：
文献类型：
--
作者：
Bonder MJ;Kasela S;Kals M;Tamm R;Lokk K;Barragan I;Buurman WA;Deelen P;Greve JW;Ivanov M;Rensen SS;van Vliet-Ostaptchouk JV;Wolfs MG;Fu J;Hofker MH;Wijmenga C;Zhernakova A;Ingelman-Sundberg M;Franke L;Milani L
一般来说，肝脏在维持体内平衡和健康方面起着核心作用。然而，肝脏基因表达存在大量的个体间差异，尽管已经确定了许多遗传因素，但对表观遗传因素知之甚少。通过分析14个胎儿肝脏和181个成人肝脏的甲基化组和转录组，我们鉴定出657个具有成人特异性表达的差异甲基化基因，这些基因富集于HNF1A和HNF4A转录因子结合位点。我们还鉴定出1,000个胎儿肝脏特异性基因，这些基因富集于GATA1、STAT5A、STAT5B和YY1结合位点。我们发现单核苷酸多态性对甲基化水平（28,447个独特的CpG位点（meQTL））和基因表达水平（526个独特的基因（eQTL））有很强的肝脏特异性影响，错误发现率(FDR) < 0.05。在526个独特的eQTL相关基因中，293个基因不仅与遗传变异显著相关，而且与甲基化水平显著相关。在肌肉、皮下脂肪组织和内脏脂肪组织中分析了这些关联的组织特异性。我们观察到meQTL在组织间比eQTL更稳定，并且对于已确定的CpG甲基化和基因表达之间的关联具有很强的组织特异性。我们的分析产生了一个涉及肝脏基因表达调控的综合因素资源，并使我们能够估计基因表达变异的比例，这可能归因于遗传和表观遗传变异，这对于理解药物反应的差异和肝脏疾病的病因至关重要。本文的在线版本（doi:10.1186/1471-2164-15-860）包含补充材料，可供授权用户使用。
The liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors. By analyzing the methylomes and transcriptomes of 14 fetal and 181 adult livers, we identified 657 differentially methylated genes with adult-specific expression, these genes were enriched for transcription factor binding sites of HNF1A and HNF4A. We also identified 1,000 genes specific to fetal liver, which were enriched for GATA1, STAT5A, STAT5B and YY1 binding sites. We saw strong liver-specific effects of single nucleotide polymorphisms on both methylation levels (28,447 unique CpG sites (meQTL)) and gene expression levels (526 unique genes (eQTL)), at a false discovery rate (FDR) < 0.05. Of the 526 unique eQTL associated genes, 293 correlated significantly not only with genetic variation but also with methylation levels. The tissue-specificities of these associations were analyzed in muscle, subcutaneous adipose tissue and visceral adipose tissue. We observed that meQTL were more stable between tissues than eQTL and a very strong tissue-specificity for the identified associations between CpG methylation and gene expression. Our analyses generated a comprehensive resource of factors involved in the regulation of hepatic gene expression, and allowed us to estimate the proportion of variation in gene expression that could be attributed to genetic and epigenetic variation, both crucial to understanding differences in drug response and the etiology of liver diseases. The online version of this article (doi:10.1186/1471-2164-15-860) contains supplementary material, which is available to authorized users.
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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：
3.9
作者：
Kacevska, Marina;Ivanov, Maxim;Ingelman-Sundberg, Magnus
通讯作者：
Ingelman-Sundberg, Magnus
影响因子：
4.5
作者：
Innocenti F;Cooper GM;Stanaway IB;Gamazon ER;Smith JD;Mirkov S;Ramirez J;Liu W;Lin YS;Moloney C;Aldred SF;Trinklein ND;Schuetz E;Nickerson DA;Thummel KE;Rieder MJ;Rettie AE;Ratain MJ;Cox NJ;Brown CD
通讯作者：
Brown CD
影响因子：
4.4
作者：
Lee JS;Ward WO;Knapp G;Ren H;Vallanat B;Abbott B;Ho K;Karp SJ;Corton JC
通讯作者：
Corton JC
影响因子：
13.5
作者：
Chen, Wei-Dong;Fu, Xianghui;Dong, Bingning;Wang, Yan-Dong;Shiah, Steven;Moore, David D.;Huang, Wendong
通讯作者：
Huang, Wendong