Hepatic gene expression variations in response to high-fat diet-induced impaired glucose tolerance using RNAseq analysis in collaborative cross mouse population
Hepatic gene expression variations in response to high-fat diet-induced impaired glucose tolerance using RNAseq analysis in collaborative cross mouse population
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DOI：
10.1007/s00335-019-09816-1
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发表时间：
2019-10-24
期刊：
影响因子：
2.5
通讯作者：
Iraqi, Fuad A.
中科院分区：
文献类型：
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作者：
Abu-Toamih Atamni, H. J.;Kontogianni, G.;Iraqi, Fuad A.
已知肝脏基因表达在健康和2型糖尿病之间存在差异。识别这些变异将为基因靶向治疗的发展提供更好的知识。本研究的目的是评估饮食诱导的肝脏基因表达的敏感与耐药CC系T2 D的发展。在高脂肪饮食（42%脂肪）12周后，对41个不同CC系（两种性别）的糖尿病和非糖尿病小鼠的84个肝脏进行下一代RNA测序。数据分析显示，糖尿病小鼠与非糖尿病小鼠肝脏基因表达存在显著差异，并具有显著的性别效应，其中601个基因在总体人群（雄性和雌性）中差异表达（DE），718个基因在雌性小鼠中，599个基因在雄性小鼠中。对于整个人群，最优先的DE候选基因是Lepr，Ins 2，Mb，Ckm，Mrap 2和Ckmt 2;对于仅女性组，Hdc，Serpina 12，Socs 1，Socs 2和Mb，而对于仅男性组，Serpine 1，Mb，Ren 1，Slc 4a 1和Atp 2a 1。性别差异的数据分析显示，健康人群中有193个DE基因（上图：Lepr、Cav 1、Socs 2、Abcg 2和Col 5a 3），糖尿病女性与男性之间有389个DE基因（上图：Lepr、Clps、Ins 2、Cav 1和Mrap 2）。此外，整合基因表达结果与先前公布的QTL，我们确定了显着的变异定位在染色体上的位置36-49 Mb，62-71 Mb，和79-99 Mb，分别在第9，11和12号染色体。我们的研究结果强调了T2 D发展的复杂性，并受到宿主复杂遗传因素的显著控制。此外，我们还证明了男性和女性在健康期间的显著性别差异，并在疾病/糖尿病期间增加到一定程度。总而言之，为进一步的研究打开大门的目标是发现有效的性别特异性和个性化的预防和治疗方法。
Hepatic gene expression is known to differ between healthy and type 2 diabetes conditions. Identifying these variations will provide better knowledge to the development of gene-targeted therapies. The aim of this study is to assess diet-induced hepatic gene expression of susceptible versus resistant CC lines to T2D development. Next-generation RNA-sequencing was performed for 84 livers of diabetic and non-diabetic mice of 41 different CC lines (both sexes) following 12 weeks on high-fat diet (42% fat). Data analysis revealed significant variations of hepatic gene expression in diabetic versus non-diabetic mice with significant sex effect, where 601 genes were differentially expressed (DE) in overall population (males and females), 718 genes in female mice, and 599 genes in male mice. Top prioritized DE candidate genes were Lepr, Ins2, Mb, Ckm, Mrap2, and Ckmt2 for the overall population; for females-only group were Hdc, Serpina12, Socs1, Socs2, and Mb, while for males-only group were Serpine1, Mb, Ren1, Slc4a1, and Atp2a1. Data analysis for sex differences revealed 193 DE genes in health (Top: Lepr, Cav1, Socs2, Abcg2, and Col5a3), and 389 genes DE between diabetic females versus males (Top: Lepr, Clps, Ins2, Cav1, and Mrap2). Furthermore, integrating gene expression results with previously published QTL, we identified significant variants mapped at chromosomes at positions 36-49 Mb, 62-71 Mb, and 79-99 Mb, on chromosomes 9, 11, and 12, respectively. Our findings emphasize the complexity of T2D development and that significantly controlled by host complex genetic factors. As well, we demonstrate the significant sex differences between males and females during health and increasing to extent levels during disease/diabetes. Altogether, opening the venue for further studies targets the discovery of effective sex-specific and personalized preventions and therapies.