PLOS ONE2013-12-27 10:46 PM

A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue 6个月运动干预影响人类脂肪组织中的全基因组DNA甲基化模式

Abstract Epigenetic mechanisms are implicated in gene regulation and the development of different diseases. The epigenome differs between cell types and has until now only been characterized for a few human tissues. Environmental factors potentially alter the epigenome. Here we describe the genome-wide pattern of DNA methylation in human adipose tissue from 23 healthy men, with a previous low level of physical activity, before and after a six months exercise intervention. We also investigate the differences in adipose tissue DNA methylation between 31 individuals with or without a family history of type 2 diabetes. DNA methylation was analyzed using Infinium HumanMethylation450 BeadChip, an array containing 485,577 probes covering 99% RefSeq genes. Global DNA methylation changed and 17,975 individual CpG sites in 7,663 unique genes showed altered levels of DNA methylation after the exercise intervention (q<0.05). Differential mRNA expression was present in 1/3 of gene regions with altered DNA methylation, including RALBP1, HDAC4 and NCOR2 (q<0.05). Using a luciferase assay, we could show that increased DNA methylation in vitro of the RALBP1 promoter suppressed the transcriptional activity (p = 0.03). Moreover, 18 obesity and 21 type 2 diabetes candidate genes had CpG sites with differences in adipose tissue DNA methylation in response to exercise (q<0.05), including TCF7L2 (6 CpG sites) and KCNQ1 (10 CpG sites). A simultaneous change in mRNA expression was seen for 6 of those genes. To understand if genes that exhibit differential DNA methylation and mRNA expression in human adipose tissue in vivo affect adipocyte metabolism, we silenced Hdac4 and Ncor2 respectively in 3T3-L1 adipocytes, which resulted in increased lipogenesis both in the basal and insulin stimulated state. In conclusion, exercise induces genome-wide changes in DNA methylation in human adipose tissue, potentially affecting adipocyte metabolism. 论文摘要 表观遗传机制与基因调控及不同疾病的发展均有牵连。表观基因在不同细胞类型之间的也有所不同,并且至今为止仅仅只被少数人类组织作为其特征。环境因素能潜在地改变表观基因。我们选取了23名先前具有较低体力活动特征的男性作为样本,对其进行为期6个月的运动干预,然后描述这些样本脂肪组织中DNA甲基化的全基因组模式在干预前后的变化。我们也调查了31个有或无2型糖尿病家族史的个体样本之间脂肪组织DNA甲基化的差异。我们使用Infinium HumanMethylation450 BeadChip这一甲基化芯片对DNA甲基化进行了分析,该甲基化芯片队列含有485577个探头,覆盖99 %的RefSeq基因阵列。整体的DNA甲基化发生了变化,在7,663个独特基因里的 17,975个单独的CpG位点表明在进行运动干预后(q < 0.05)DNA甲基化发生了程度上的改变。包括RALBP1 , HDAC4和NCOR2 (Q < 0.05 )在内的不同转录基因的表达通过改变的DNA甲基化在基因区域的1/3中表达出来。使用荧光素酶测定法,我们可以证明在RALBP1启动子体外增长的DNA甲基化抑制了转录的活性(p值= 0.03)。此外, 18个肥胖症和21个2型糖尿病候选者基因具有表现出脂肪组织DNA甲基化差异且对锻炼干预作出反应(q <0.05)的CpG位点,其中包括TCF7L2 (6 个CpG位点)和KCNQ1 (10个 CpG位点)。我们发现这些基因中的6个在转录基因表达中同时发生了改变。为了了解在人体内脂肪组织的那些表现出不同DNA甲基化和转录基因表达的基因是否会影响脂肪细胞新陈代谢,我们抑制了3T3 -L1脂肪细胞中HDAC4和Ncor2基因的表达 ,这使得无论是在基础状态下还是在胰岛素刺激状态下脂肪合成都表现出了增强。总之运动会诱发在人体脂肪组织中的DNA甲基化的全基因组改变,这将潜在影响脂肪细胞的新陈代谢。 Author Summary Given the important role of epigenetics in gene regulation and disease development, we here present the genome-wide DNA methylation pattern of 476,753 CpG sites in adipose tissue obtained from healthy men. Since environmental factors potentially change metabolism through epigenetic modifications, we examined if a six months exercise intervention alters the DNA methylation pattern as well as gene expression in human adipose tissue. Our results show that global DNA methylation changes and 17,975 individual CpG sites alter the levels of DNA methylation in response to exercise. We also found differential DNA methylation of 39 candidate genes for obesity and type 2 diabetes in human adipose tissue after exercise. Additionally, we provide functional proof that genes, which exhibit both differential DNA methylation and gene expression in human adipose tissue in response to exercise, influence adipocyte metabolism. Together, this study provides the first detailed map of the genome-wide DNA methylation pattern in human adipose tissue and links exercise to altered adipose tissue DNA methylation, potentially affecting adipocyte metabolism. 作者总结 鉴于表观遗传学在基因调控及疾病发展中的重要作用,我们在此展示了从健康男性样本体内获得的476753 个位于脂肪组织中的CpG位点的全基因组DNA甲基化模式。由于环境因素能通过表观遗传修饰潜在改变新陈代谢,我们检验了是否6个月的运动干预能改变人体脂肪组织中的DNA甲基化模式以及基因表达。我们的研究结果表明作为对运动干预的应对措施,整体DNA甲基化发生了变化且17,975个单独的CpG位点改变了DNA甲基化的程度。在进行运动干预后,我们还在样本人体脂肪组织中发现39个候选基因对肥胖和2型糖尿病表现出了差异性的DNA甲基化。此外,我们提供了功能性证据证明了这些在人体脂肪组织中表现出不同DNA甲基化和基因表达来作为对运动干预的响应的基因会影响脂肪细胞的新陈代谢。总而言之,这项研究首次提供了在人体脂肪组织中全基因组DNA甲基化模式的详尽图谱且表明了运动锻炼会影响脂肪组织DNA甲基化发生变化,潜在影响了脂肪细胞的新陈代谢。

KEYWORDS

SHARE & LIKE

COMMENTS

ABOUT THE AUTHOR

PLOS ONE

0 Following 5 Fans 0 Projects 90 Articles

SIMILAR ARTICLES

AbstractAgencies that fund scientific research must choose: is it more effective to give large grants to a few elite researchers, or small grants to ma

Read More

Abstract The role of genetically modified (GM) crops for food security is the subject of public controversy. GM crops could contribute to food product

Read More

Abstract 论文摘要 Background Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United State

Read More

AbstractThe U.S. National Institutes of Health (NIH) budget expansion from 1998 through 2003 increased demand for biomedical research, raising relative

Read More

Abstract Kawaii (a Japanese word meaning “cute”) things are popular because they produce positive feelings. However, their effect on behavior remains

Read More

Abstract The diversity of life is one of the most striking aspects of our planet; hence knowing how many species inhabit Earth is among the most funda

Read More

Abstract Lateralized brain regions subserve functions such as language and visuospatial processing. It has been conjectured that individuals may be le

Read More

Abstract Background and Aims Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis ind

Read More