Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in monozygotic twins discordant for obesity and liver fat.
Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in monozygotic twins discordant for obesity and liver fat.
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DOI：
10.1186/s13148-015-0073-5
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发表时间：
2015
影响因子：
5.7
通讯作者：
Kaprio J
中科院分区：
文献类型：
--
作者：
Ollikainen M;Ismail K;Gervin K;Kyllönen A;Hakkarainen A;Lundbom J;Järvinen EA;Harris JR;Lundbom N;Rissanen A;Lyle R;Pietiläinen KH;Kaprio J
目前肥胖和相关疾病的流行需要迅速采取行动，以更好地了解遗传和环境因素影响人类代谢健康的机制。单卵（MZ）双胞胎对显示不一致的肥胖表明，表观遗传的影响代表这样的机制之一。我们研究了30对体重指数（BMI;平均配对内BMI差异：5.4 ± 2.0 kg/m2）不一致的临床健康年轻成年MZ双胞胎对的全基因组白细胞DNA甲基化变异。有没有差异甲基化胞嘧啶鸟嘌呤（CpG）的网站之间的共双胞胎BMI不一致。然而，根据肝脏脂肪堆积水平对双胞胎进行分层，发现两个表观遗传学高度不同的组。只有在体重较重的双胞胎肝脏脂肪过多（n = 13对双胞胎）时，才观察到双胞胎之间的显著DNA甲基化差异（n = 1，236个CpG位点（CpG））。这种不健康的肥胖模式伴随着胰岛素抵抗和低度炎症。差异甲基化的CpG包括23个已知与肥胖、肝脏脂肪、2型糖尿病（T2 DM）和代谢综合征相关的基因，以及潜在的新代谢基因。差异甲基化的CpG位点在启动子、绝缘子、异染色质和阻遏区域过度表达。基于重叠组蛋白标记的预测，抑制和弱转录位点显着更经常低甲基化，而强增强子和活性启动子的位点高甲基化。此外，在维生素，氨基酸，脂肪酸，硫，和肾素-血管紧张素代谢途径的差异甲基化基因的显着聚类观察。白细胞中的甲基化在与代谢紊乱相关的肥胖中发生改变，我们的研究结果表明了肥胖和肥胖相关并发症中的几个新的候选基因和途径。本文的在线版本（doi：10.1186/s13148-015-0073-5）包含补充材料，可供授权用户使用。
The current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans. Monozygotic (MZ) twin pairs showing discordance for obesity suggest that epigenetic influences represent one such mechanism. We studied genome-wide leukocyte DNA methylation variation in 30 clinically healthy young adult MZ twin pairs discordant for body mass index (BMI; average within-pair BMI difference: 5.4 ± 2.0 kg/m2). There were no differentially methylated cytosine-guanine (CpG) sites between the co-twins discordant for BMI. However, stratification of the twin pairs based on the level of liver fat accumulation revealed two epigenetically highly different groups. Significant DNA methylation differences (n = 1,236 CpG sites (CpGs)) between the co-twins were only observed if the heavier co-twins had excessive liver fat (n = 13 twin pairs). This unhealthy pattern of obesity was coupled with insulin resistance and low-grade inflammation. The differentially methylated CpGs included 23 genes known to be associated with obesity, liver fat, type 2 diabetes mellitus (T2DM) and metabolic syndrome, and potential novel metabolic genes. Differentially methylated CpG sites were overrepresented at promoters, insulators, and heterochromatic and repressed regions. Based on predictions by overlapping histone marks, repressed and weakly transcribed sites were significantly more often hypomethylated, whereas sites with strong enhancers and active promoters were hypermethylated. Further, significant clustering of differentially methylated genes in vitamin, amino acid, fatty acid, sulfur, and renin-angiotensin metabolism pathways was observed. The methylome in leukocytes is altered in obesity associated with metabolic disturbances, and our findings indicate several novel candidate genes and pathways in obesity and obesity-related complications. The online version of this article (doi:10.1186/s13148-015-0073-5) contains supplementary material, which is available to authorized users.
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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.
影响因子：
3.5
作者：
Dempster EL;Pidsley R;Schalkwyk LC;Owens S;Georgiades A;Kane F;Kalidindi S;Picchioni M;Kravariti E;Toulopoulou T;Murray RM;Mill J
通讯作者：
Mill J
影响因子：
10.6
作者：
Dempster EL;Wong CC;Lester KJ;Burrage J;Gregory AM;Mill J;Eley TC
通讯作者：
Eley TC
影响因子：
3.7
作者：
Comuzzie AG;Cole SA;Laston SL;Voruganti VS;Haack K;Gibbs RA;Butte NF
通讯作者：
Butte NF
影响因子：
6.2
作者：
Bogl, Leonie H.;Latvala, Antti;Kaprio, Jaakko;Sovijarvi, Olli;Rissanen, Aila;Pietilainen, Kirsi H.
通讯作者：
Pietilainen, Kirsi H.