The Gene Regulatory Footprint of Aging Highlights Conserved Central Regulators

Many genes and pathways have been linked to aging, yet our understanding of underlying molecular mechanisms is still lacking. Here, we measure changes in the transcriptome, histone modifications and DNA-methylome in three metabolic tissues of adult and aged mice. Transcriptome and methylome changes dominate the liver aging footprint, whereas heart and muscle globally increase chromatin accessibility especially in aging pathways. In mouse and human data from multiple tissues and regulatory layers, age-related transcription factor expression changes and binding site enrichment converge on putative aging modulators, including ZIC1, CXXC1, HMGA1, MECP2, SREBF1, SREBF2, ETS2, ZBTB7A, and ZNF518B. Using Mendelian randomization, we establish possible epidemiological links between expression of some of these transcription factors or their targets, including CXXC1, ZNF518B, and BBC3, and longevity. We conclude that conserved modulators are at the core of the molecular footprint of aging, and variation in tissue-specific expression of some may affect human longevity. This repository containes the R code used to reproduce the findings and figures in the Bou Sleiman et al., 2020 Cell Reports publication. Please contact the authors for specific questions.

已有众多基因与通路与衰老过程相关联，但目前学界对其背后的分子机制仍缺乏充分认知。本研究对成年与衰老小鼠的三种代谢组织的转录组、组蛋白修饰及DNA甲基化组变化进行了检测。转录组与甲基化组变化是肝脏衰老特征的主要构成，而心脏与肌肉组织则整体提升了染色质可及性，尤其在衰老相关通路中。在小鼠与人类的多组织、多调控层数据中，衰老相关转录因子的表达变化及其结合位点富集分析，共同指向一批潜在的衰老调控因子，包括ZIC1、CXXC1、HMGA1、MECP2、SREBF1、SREBF2、ETS2、ZBTB7A以及ZNF518B。借助孟德尔随机化（Mendelian randomization）分析，我们证实了部分此类转录因子或其靶基因（如CXXC1、ZNF518B与BBC3）的表达与人类寿命之间存在潜在的流行病学关联。本研究结论认为，保守的调控因子构成了衰老分子特征的核心，其中部分因子的组织特异性表达差异可能会影响人类寿命。本仓库包含用于复现Bou Sleiman等人2020年发表于《Cell Reports》的研究成果与配套图表的R代码。如有具体疑问，请联系论文作者。