Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging.
Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging.
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DOI：
10.1101/gad.233221.113
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发表时间：
2014-02-15
影响因子：
10.5
通讯作者：
Tyler JK
中科院分区：
文献类型：
--
作者：
Hu Z;Chen K;Xia Z;Chavez M;Pal S;Seol JH;Chen CC;Li W;Tyler JK
所有的真核细胞分裂的次数都是有限的，但复制性衰老的机制基础仍然不清楚。在这里，泰勒和他的同事们研究了老化对芽殖酵母染色质结构和DNA不稳定性的影响。加标对照的使用揭示了衰老期间核小体占据率的总体降低。老化过程中组蛋白的丢失导致所有酵母基因的转录诱导。此外，作者证明了衰老过程中DNA损伤、逆转录转座、大规模染色体重排和易位水平的升高。所有的真核细胞都分裂有限的次数，尽管这种复制性衰老的机制基础仍然不清楚。复制老化伴随着组蛋白水平的降低，这是芽殖酵母老化的原因。在这里，我们表明，核小体占有率下降了50%，在整个基因组复制老化过程中使用穗控制微球菌核酸酶消化测序。此外，核小体变得不太好定位或移动到预测更好地容纳组蛋白八聚体的序列。老化过程中组蛋白的丢失导致所有酵母基因的转录诱导。通常被启动子核小体抑制的基因被诱导最多，伴随着从其启动子的优先核小体丢失。我们还发现，在衰老过程中，DNA链断裂、线粒体DNA转移到核基因组、大规模染色体改变、易位和逆转录转座的水平升高。
All eukaryotic cells divide a finite number of times, yet the mechanistic basis of replicative aging remains unclear. Here, Tyler and colleagues investigate the effects of aging on chromatin structure and DNA instability in budding yeast. The use of spike-in controls reveals a global reduction in nucleosome occupancy during aging. Histone loss during aging leads to transcriptional induction of all yeast genes. Furthermore, the authors demonstrate elevated levels of DNA damage, retrotransposition, large-scale chromosome rearrangement, and translocation during aging. All eukaryotic cells divide a finite number of times, although the mechanistic basis of this replicative aging remains unclear. Replicative aging is accompanied by a reduction in histone protein levels, and this is a cause of aging in budding yeast. Here we show that nucleosome occupancy decreased by 50% across the whole genome during replicative aging using spike-in controlled micrococcal nuclease digestion followed by sequencing. Furthermore, nucleosomes became less well positioned or moved to sequences predicted to better accommodate histone octamers. The loss of histones during aging led to transcriptional induction of all yeast genes. Genes that are normally repressed by promoter nucleosomes were most induced, accompanied by preferential nucleosome loss from their promoters. We also found elevated levels of DNA strand breaks, mitochondrial DNA transfer to the nuclear genome, large-scale chromosomal alterations, translocations, and retrotransposition during aging.