Genome-wide expression profiles in young and old mouse liver [RNA-seq]

Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that de-repression of the nuclear receptors PPARα, PPARγ, and LXRα in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and for novel candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix factor Foxa2 and nuclear receptor co-repressor Hdac3 exhibit reciprocal binding pattern at PPARα targets contributing to gene expression changes that lead to steatosis in aged liver. Genome-wide expression profiles (RNA-Seq) from young (3 months) and old (21 months) mouse livers机体衰老会伴随生理机能受损，在包括肝脏在内的胰岛素响应组织中，此类损伤会使个体更易罹患代谢性疾病。然而，上述衰老相关变化背后的分子机制目前仍大多尚未明确。本研究对年轻（3月龄）与年老（21月龄）小鼠肝脏中的RNA及染色质组织全基因组图谱进行了分析。转录组变化显示，年老小鼠肝脏中核受体（nuclear receptor）PPARα、PPARγ及LXRα的去抑制作用，会激活调控脂质合成与储存的靶基因；而衰老相关的核小体占据率变化，则与两类结合位点相关：一类是已知调控因子（叉头框转录因子与核受体）的结合位点，另一类是与核纤层（nuclear lamina）相关的新型候选调控因子——组蛋白去乙酰化酶3（HDAC3）与血清反应因子（SRF）的结合位点，上述新型因子被证实可调控衰老肝脏的代谢功能。翼螺旋转录因子Foxa2与核受体辅阻遏物HDAC3在PPARα靶位点上呈现反向结合模式，该模式会促成基因表达变化，进而引发衰老肝脏的脂肪变性。本研究同时包含年轻（3月龄）与年老（21月龄）小鼠肝脏的全基因组表达谱（RNA测序（RNA-Seq））数据。