Bochkis Irina M, Przybylski Dariusz, Chen Jenny, Regev Aviv
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell Rep. 2014 Nov 6;9(3):996-1006. doi: 10.1016/j.celrep.2014.09.048. Epub 2014 Oct 23.
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 derepression 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 candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix transcription factor Foxa2 and nuclear receptor corepressor Hdac3 exhibit a reciprocal binding pattern at PPARα targets contributing to gene expression changes that lead to steatosis in aged liver.
衰老伴随着生理功能的损伤，在包括肝脏在内的胰岛素反应性组织中，这种损伤会使个体易患代谢性疾病。然而，这些变化背后的分子机制在很大程度上仍然未知。在这里，我们分析了年轻（3个月）和年老（21个月）小鼠肝脏中RNA和染色质组织的全基因组图谱。转录变化表明，老年小鼠肝脏中核受体PPARα、PPARγ和LXRα的去抑制导致调节脂质合成和储存的靶标的激活，而核小体占据率的年龄依赖性变化与已知调节因子（叉头因子和核受体）以及与核纤层相关的候选因子（Hdac3和Srf）的结合位点有关，这些候选因子被认为控制着衰老肝脏的代谢功能。翼状螺旋转录因子Foxa2和核受体共抑制因子Hdac3在PPARα靶标上表现出相互结合模式，这有助于导致老年肝脏脂肪变性的基因表达变化。
