Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Nat Commun. 2011 Aug 16;2:433. doi: 10.1038/ncomms1443.
In Saccharomyces cerevisiae, the repressive chromatin environment at telomeres gives rise to telomere position effect (TPE), the epigenetic silencing of telomere-proximal genes. Chromatin-modifying factors that control TPE in yeast have been extensively studied, and, among these, the lifespan regulator and silencing protein Sir2 has a pivotal role. In contrast, the factors that generate and maintain silent telomeric chromatin in human cells remain largely unknown. Here we show that the Sir2 family member SIRT6 is required for maintenance of TPE in human cells. RNAi-mediated depletion of SIRT6 abrogates silencing of both an integrated telomeric transgene and an endogenous telomere-proximal gene. Moreover, enhanced telomeric silencing in response to telomere elongation is associated with increased repressive chromatin marks, and this heterochromatic milieu is lost in SIRT6-deficient cells. Together, these findings establish a new role for SIRT6 in regulating an ageing-associated epigenetic silencing process and provide new mechanistic insight into chromatin silencing at telomeres.
在酿酒酵母中，端粒处的抑制性染色质环境导致端粒位置效应（TPE），即端粒附近基因的表观遗传沉默。已经对控制酵母中 TPE 的染色质修饰因子进行了广泛研究，其中寿命调节剂和沉默蛋白 Sir2 起着关键作用。相比之下，在人类细胞中产生和维持沉默端粒染色质的因子在很大程度上仍是未知的。在这里，我们表明 Sir2 家族成员 SIRT6 是维持人类细胞中 TPE 所必需的。通过 RNAi 介导的 SIRT6 消耗，会破坏整合的端粒转基因和内源性端粒附近基因的沉默。此外，端粒延长引起的端粒沉默增强与增加的抑制性染色质标记相关，而在 SIRT6 缺陷细胞中这种异染色质环境会丢失。总之，这些发现为 SIRT6 在调节与衰老相关的表观遗传沉默过程中的新作用提供了依据，并为端粒处的染色质沉默提供了新的机制见解。
