Transcriptional and epigenetic landscape of the mouse intestine during aging identifies key molecular drivers of aging -associated dysfunctions and diseases. [Total RNA-seq - Lgr5]

Aging is a complex multifactorial process leading to the loss of tissue/organ functionality and to an increase in disease risk. Aging-related intestinal dysfunctions include loss of barrier integrity, altered stress responses, nutrient malabsorption, and cancer formation. Many molecular mechanisms related to dysfunction and diseases are well-known (e.g. in cancer), however how aging impact on them before the occurrence of dysfunctions and diseases is poorly understood. In this study, we applied a multi-layered omics-approach to characterize the transcriptional and the epigenetic landscape of mouse intestinal epithelium during aging. We found gender and cell-type specific transcriptional and epigenetic alterations on key pathways and genes linked to intestinal dysfunctions, stem cell aging, organismal lifespan and cancer. Moreover, we identified a switch in the composition of the old intestinal stem cell subpopulations, represented by a drift towards a more secretory lineage committed (and less stem) state accompanied by functional epigenetic alterations. Transcriptional and epigenetic landscape of the mouse intestine during aging.衰老是一类复杂的多因素生理进程，可导致组织与器官功能衰退，并提升疾病罹患风险。衰老相关的肠道功能异常包括屏障完整性丧失、应激反应失调、营养吸收不良以及癌变。目前学界已明确诸多与功能异常及疾病相关的分子机制（例如癌症领域），但衰老在功能异常与疾病发生前对这些机制的具体影响，仍未得到充分阐释。本研究采用多层组学（multi-layered omics）方法，对衰老过程中小鼠肠道上皮细胞的转录组与表观遗传图谱进行系统性表征。研究发现，与肠道功能异常、干细胞衰老、机体寿命及癌症相关的关键通路与基因，存在性别与细胞类型特异性的转录组及表观遗传改变。此外，本研究还鉴定出衰老肠道干细胞亚群的组成发生显著转变：其特征为向更偏向分泌谱系定型（干性更低）的状态偏移，同时伴随功能性表观遗传改变。本数据集为衰老过程中小鼠肠道的转录组与表观遗传图谱。