Hypothalamic transcriptome of male mice on high fat diet, from 99 strains

Previous studies had shown that integration of genome wide expression profiles, in metabolic tissues, with genetic and phenotypic variance, provided valuable insight into the underlying molecular mechanisms. We used RNA-Seq to characterize hypothalamic transcriptome in 99 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP), a reference resource population for cardiovascular and metabolic traits. We report numerous novel transcripts supported by proteomic analyses, as well as novel non coding RNAs. High resolution genetic mapping of transcript levels in HMDP, reveals both local and trans expression Quantitative Trait Loci (eQTLs) demonstrating 2 trans eQTL "hotspots" associated with expression of hundreds of genes. We also report thousands of alternative splicing events regulated by genetic variants. Finally, comparison with about 150 metabolic and cardiovascular traits revealed many highly significant associations. Our data provides a rich resource for understanding the many physiologic functions mediated by the hypothalamus and their genetic regulation. 282 samples, 3 biological replicates per strain

既往研究表明，将代谢组织的全基因组表达谱与遗传及表型变异进行整合，可深入揭示潜在的分子机制。本研究利用RNA测序（RNA-Seq）对杂交小鼠多样性面板（Hybrid Mouse Diversity Panel, HMDP）中的99个近交系小鼠下丘脑转录组进行表征；该面板是用于心血管和代谢性状研究的参考资源群体。本研究报道了大量得到蛋白质组学分析支持的新型转录本，以及新型非编码RNA（non-coding RNAs）。对HMDP中转录水平开展的高分辨率遗传定位，共鉴定出顺式和反式表达数量性状位点（expression Quantitative Trait Loci, eQTLs），其中存在2个与数百个基因表达相关的反式eQTL热点区域。本研究同时报道了数千个受遗传变异调控的可变剪接事件。最后，通过与约150项代谢和心血管性状进行对比，本研究发现了大量极具统计学显著性的关联信号。本研究数据集为解析下丘脑介导的众多生理功能及其遗传调控机制提供了宝贵资源。共包含282个样本，每个品系设置3个生物学重复。