Type 2 diabetes and obesity induce similar transcriptional reprogramming in human myocytes.
Type 2 diabetes and obesity induce similar transcriptional reprogramming in human myocytes.
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DOI：
10.1186/s13073-017-0432-2
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发表时间：
2017-05-25
期刊：
影响因子：
12.3
通讯作者：
Nielsen J
中科院分区：
文献类型：
--
作者：
Väremo L;Henriksen TI;Scheele C;Broholm C;Pedersen M;Uhlén M;Pedersen BK;Nielsen J
骨骼肌是参与2型糖尿病（T2D）发展的主要组织之一。肥胖和T2D之间的密切联系使得很难分离出单独归因于该疾病的特定影响。因此，在这里，我们着手确定和表征与T2D或肥胖独立相关的肌细胞的内在特性。我们使用因子设计（健康/T2D和非肥胖/肥胖）生成并分析了来自24名人类受试者的原代分化肌管的RNA-seq数据，以确定每个特定因素对全基因组转录的影响。这种设置使我们能够识别源自肌肉前体细胞并保留在相应的肌细胞中的内在特性。采用生物信息学和统计学方法，包括差异表达分析、基因集分析和代谢网络分析来表征不同的肌细胞。我们发现单独与肥胖相关的转录程序与T2D特异性诱导的转录程序惊人地相似。我们确定了一个候选的表观遗传机制，H3K27me3组蛋白甲基化，介导这些转录特征。T2D和肥胖与肌肉生成失调、肌肉功能下调、炎症和细胞外基质成分上调独立相关。代谢网络分析发现，在T2D而非肥胖中，参与鞘脂代谢的特定代谢物亚网络受到转录调节。我们的研究结果确定了肌细胞的固有特征，作为体内表型的记忆，不受糖尿病或肥胖细胞外环境的影响，突出了它们在T2D发展中的重要性。本文的在线版本（doi:10.1186/s13073-017-0432-2）包含补充材料，可供授权用户使用。
Skeletal muscle is one of the primary tissues involved in the development of type 2 diabetes (T2D). The close association between obesity and T2D makes it difficult to isolate specific effects attributed to the disease alone. Therefore, here we set out to identify and characterize intrinsic properties of myocytes, associated independently with T2D or obesity. We generated and analyzed RNA-seq data from primary differentiated myotubes from 24 human subjects, using a factorial design (healthy/T2D and non-obese/obese), to determine the influence of each specific factor on genome-wide transcription. This setup enabled us to identify intrinsic properties, originating from muscle precursor cells and retained in the corresponding myocytes. Bioinformatic and statistical methods, including differential expression analysis, gene-set analysis, and metabolic network analysis, were used to characterize the different myocytes. We found that the transcriptional program associated with obesity alone was strikingly similar to that induced specifically by T2D. We identified a candidate epigenetic mechanism, H3K27me3 histone methylation, mediating these transcriptional signatures. T2D and obesity were independently associated with dysregulated myogenesis, down-regulated muscle function, and up-regulation of inflammation and extracellular matrix components. Metabolic network analysis identified that in T2D but not obesity a specific metabolite subnetwork involved in sphingolipid metabolism was transcriptionally regulated. Our findings identify inherent characteristics in myocytes, as a memory of the in vivo phenotype, without the influence from a diabetic or obese extracellular environment, highlighting their importance in the development of T2D. The online version of this article (doi:10.1186/s13073-017-0432-2) contains supplementary material, which is available to authorized users.