Nilsson Emma, Matte Ashok, Perfilyev Alexander, de Mello Vanessa D, Käkelä Pirjo, Pihlajamäki Jussi, Ling Charlotte
Epigenetics and Diabetes Unit (E.N., A.P., C.L.), Department of Clinical Sciences, Lund University Diabetes Centre, 205 02 Malmö, Sweden; Department of Clinical Nutrition (A.M., V.D.d.M., J.P.), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, and Clinical Nutrition and Obesity Center (J.P.), Kuopio University Hospital, 70211 Kuopio, Finland.
J Clin Endocrinol Metab. 2015 Nov;100(11):E1491-501. doi: 10.1210/jc.2015-3204. Epub 2015 Sep 29.
Epigenetic variation may contribute to the development of complex metabolic diseases such as type 2 diabetes (T2D). Hepatic insulin resistance is a hallmark of T2D. However, it remains unknown whether epigenetic alterations take place in the liver from diabetic subjects. Therefore, we investigated the genome-wide DNA methylation pattern in the liver from subjects with T2D and nondiabetic controls and related epigenetic alterations to gene expression and circulating folate levels.
Liver biopsies were obtained from 35 diabetic and 60 nondiabetic subjects, which are part of the Kuopio Obesity Surgery Study. The genome-wide DNA methylation pattern was analyzed in the liver using the HumanMethylation450 BeadChip. RNA expression was analyzed from a subset of subjects using the HumanHT-12 Expression BeadChip.
After correction for multiple testing, we identified 251 individual CpG sites that exhibit differential DNA methylation in liver obtained from T2D compared with nondiabetic subjects (Q < .05). These include CpG sites annotated to genes that are biologically relevant to the development of T2D such as GRB10, ABCC3, MOGAT1, and PRDM16. The vast majority of the significant CpG sites (94%) displayed decreased DNA methylation in liver from subjects with T2D. The hypomethylation found in liver from diabetic subjects may be explained by reduced folate levels. Indeed, subjects with T2D had significantly reduced erythrocyte folate levels compared with nondiabetic subjects. We further identified 29 genes that displayed both differential DNA methylation and gene expression in human T2D liver including the imprinted gene H19.
Our study highlights the importance of epigenetic and transcriptional changes in the liver from subjects with T2D. Reduced circulating folate levels may provide an explanation for hypomethylation in the human diabetic liver.
表观遗传变异可能促成2型糖尿病（T2D）等复杂代谢性疾病的发生。肝脏胰岛素抵抗是T2D的一个标志。然而，糖尿病患者肝脏中是否发生表观遗传改变仍不清楚。因此，我们研究了T2D患者和非糖尿病对照者肝脏中的全基因组DNA甲基化模式，并将相关的表观遗传改变与基因表达和循环叶酸水平联系起来。
从35名糖尿病患者和60名非糖尿病患者身上获取肝脏活检样本，这些样本来自库奥皮奥肥胖手术研究。使用HumanMethylation450 BeadChip对肝脏中的全基因组DNA甲基化模式进行分析。使用HumanHT - 12 Expression BeadChip对部分受试者的RNA表达进行分析。
在进行多重检验校正后，我们鉴定出251个个体CpG位点，与非糖尿病受试者相比，这些位点在T2D患者的肝脏中呈现出不同的DNA甲基化（Q < 0.05）。这些位点包括注释到与T2D发生具有生物学相关性的基因的CpG位点，如GRB10、ABCC3、MOGAT1和PRDM16。绝大多数显著的CpG位点（94%）在T2D患者的肝脏中显示出DNA甲基化降低。糖尿病患者肝脏中发现的低甲基化可能由叶酸水平降低来解释。事实上，与非糖尿病受试者相比，T2D患者的红细胞叶酸水平显著降低。我们进一步鉴定出29个在人类T2D肝脏中同时呈现出DNA甲基化差异和基因表达差异的基因，包括印记基因H19。
我们的研究突出了T2D患者肝脏中表观遗传和转录变化的重要性。循环叶酸水平降低可能为人类糖尿病肝脏中的低甲基化提供一种解释。
