Sirtuins are pro-longevity genes with chromatin modulation potential, but how these properties are connected is not well understood. Here, we generated a panel of isogeneic human stem cell lines with SIRT1–SIRT7 knockouts and found that any sirtuin deficiency leads to accelerated cellular senescence. Through large-scale epigenomic analyses, we show how sirtuin deficiency alters genome organization and that genomic regions sensitive to sirtuin deficiency are preferentially enriched in active enhancers, thereby promoting interactions within topologically associated domains and the formation of de novo enhancer-promoter loops. In all sirtuin-deficient human stem cell lines, we found that chromatin contacts are rewired to promote aberrant activation of the placenta-specific gene PAPPA, which controls the pro-senescence effects associated with sirtuin deficiency and serves as a potential aging biomarker. Based on our survey of the 3D chromatin architecture, we established connections between sirtuins and potential target genes, thereby informing the development of strategies for aging interventions.

Sirtuins 是具有染色质调节潜力的长寿基因，但这些特性之间的关系尚不清楚。在这里，我们生成了一组 SIRT1-SIRT7 敲除的同基因人类干细胞系，发现任何 Sirtuin 缺陷都会导致细胞加速衰老。通过大规模表观基因组分析，我们展示了sirtuin缺乏如何改变基因组组织，并且对sirtuin缺乏敏感的基因组区域优先富集活性增强子，从而促进拓扑相关域内的相互作用以及从头增强子-启动子环的形成。在所有缺乏sirtuin的人类干细胞系中，我们发现染色质接触被重新连接以促进胎盘特异性基因PAPPA的异常激活，该基因控制与sirtuin缺乏相关的促衰老效应，并作为潜在的衰老生物标志物。根据我们对 3D 染色质结构的调查，我们建立了 Sirtuins 和潜在靶基因之间的联系，从而为衰老干预策略的制定提供信息。