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

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（Aging）是一种复杂的多因素生物学过程，可引发组织/器官功能衰退，并升高疾病罹患风险。与衰老相关的肠道功能障碍主要包括屏障完整性受损、应激反应失调、营养吸收不良以及癌症发生。目前，诸多与功能异常及疾病相关的分子机制已被阐明（例如癌症相关机制），但在功能障碍与疾病发生之前，衰老对这些机制的具体影响仍未得到充分解析。本研究采用多层组学方法（multi-layered omics-approach），对衰老过程中小鼠肠道上皮细胞的转录组与表观遗传景观进行了系统表征。研究发现，在与肠道功能障碍、干细胞衰老、机体寿命及癌症相关的关键通路与基因上，存在性别与细胞类型特异性的转录与表观遗传改变。此外，本研究还鉴定出衰老肠道干细胞的亚群组成发生了转换：表现为向更倾向于终末分泌系分化（而非干细胞维持状态）的方向漂移，同时伴随功能性表观遗传改变。衰老过程中小鼠肠道的转录组与表观遗传景观