Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels.
Sex Differences in the Methylome and Transcriptome of the Human Liver and Circulating HDL-Cholesterol Levels.
复制标题
DOI：
10.1210/jc.2018-00423
复制
发表时间：
2018-12-01
期刊：
影响因子：
--
通讯作者：
Ling C
中科院分区：
文献类型：
--
作者：
García-Calzón S;Perfilyev A;de Mello VD;Pihlajamäki J;Ling C
表观遗传学可能导致人类肝脏代谢的性别特异性差异。研究性别对人类肝脏DNA甲基化和基因表达的影响。横截面，库奥皮奥肥胖手术研究。我们用Infinium HumanMethylation 450 BeadChip分析了肥胖人群（34名男性，61名女性）肝脏中的DNA甲基化。与男性相比，女性的高密度脂蛋白（HDL）-胆固醇水平较高。用HumanHT-12 Expression BeadChip在42名参与者的子集中测量基因表达。女性在X染色体中表现出更高的平均甲基化，而男性在常染色体中表现出更高的甲基化。我们在X染色体上发现了9455个CpG位点，在常染色体上发现了33,205个CpG位点，在不同性别的肝脏中存在显著的甲基化差异（q < 0.05）。当将我们的研究结果与已发表的研究进行比较时，X染色体中肝脏甲基化的性别特异性差异中有95%也存在于胰岛和大脑中，26个常染色体位点显示肝脏和其他人体组织中存在性别特异性甲基化差异。此外，这种性别特异性甲基化在肝脏中与男性和女性之间的肝脏基因表达变化相关。值得注意的是，女性显示出更高的HDL-胆固醇水平，这与人类肝脏中更高的KDM 6A表达和表观遗传差异相关。因此，在培养的肝细胞中沉默KDM 6A降低了HDL-胆固醇水平和APOA 1表达，APOA 1是HDL颗粒的主要成分。人类肝脏在X染色体和常染色体上都存在性别特异性甲基化，这与肝脏基因表达变化和HDL-胆固醇相关。我们将KDM 6A确定为调节HDL-胆固醇水平的新靶点。表观遗传学是人类肝脏转录组性别特异性差异的重要机制。KDM 6A有助于女性和男性之间HDL-胆固醇的差异。
Epigenetics may contribute to sex-specific differences in human liver metabolism. To study the impact of sex on DNA methylation and gene expression in human liver. Cross-sectional, Kuopio Obesity Surgery Study. We analyzed DNA methylation with the Infinium HumanMethylation450 BeadChip in liver of an obese population (34 males, 61 females). Females had a higher high-density lipoprotein (HDL)–cholesterol levels compared with males. Gene expression was measured with the HumanHT-12 Expression BeadChip in a subset of 42 participants. Females displayed higher average methylation in the X-chromosome, whereas males presented higher methylation in autosomes. We found 9455 CpG sites in the X-chromosome and 33,205 sites in autosomes with significant methylation differences in liver between sexes (q < 0.05). When comparing our findings with published studies, 95% of the sex-specific differences in liver methylation in the X-chromosome were also found in pancreatic islets and brain, and 26 autosomal sites showed sex-specific methylation differences in the liver as well as in other human tissues. Furthermore, this sex-specific methylation profile in liver was associated with hepatic gene expression changes between males and females. Notably, females showed higher HDL-cholesterol levels, which were associated with higher KDM6A expression and epigenetic differences in human liver. Accordingly, silencing of KDM6A in cultured liver cells reduced HDL-cholesterol levels and APOA1 expression, which is a major component of HDL particles. Human liver has a sex-specific methylation profile in both the X-chromosome and autosomes, which associates with hepatic gene expression changes and HDL-cholesterol. We identified KDM6A as a novel target that regulates HDL-cholesterol levels. Epigenetics is an important mechanism for sex-specific differences in the transcriptome in the human liver. KDM6A contributes to the differences in HDL-cholesterol between females and males.
登录
查看更多内容
影响因子：
14.9
作者：
Khan A;Fornes O;Stigliani A;Gheorghe M;Castro-Mondragon JA;van der Lee R;Bessy A;Chèneby J;Kulkarni SR;Tan G;Baranasic D;Arenillas DJ;Sandelin A;Vandepoele K;Lenhard B;Ballester B;Wasserman WW;Parcy F;Mathelier A
通讯作者：
Mathelier A
影响因子：
21.3
作者：
Litvak, V;Dahan, N;Lev, S
通讯作者：
Lev, S
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
16.8
作者：
Lerdrup, Mads;Johansen, Jens Vilstrup;Hansen, Klaus
通讯作者：
Hansen, Klaus
影响因子：
3.8
作者：
Iwasaki, Motoki;Ono, Hiroe;Tsugane, Shoichiro
通讯作者：
Tsugane, Shoichiro