Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and human cell lines.,Aging Cell

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Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and human cell lines.
Aging Cell ( IF 8.0 ) Pub Date : 2020-03-11 , DOI: 10.1111/acel.13129
Boyue Huang ₁ , Dandan Zhong ₁ , Jie Zhu ₁ , Yongpan An ₁ , Miaomiao Gao ₁ , Shuai Zhu ₁ , Weiwei Dang ₂ , Xin Wang ₁ , Baoxue Yang _{1,

3} , Zhengwei Xie _{1,

4}

Affiliation

Histone acetyltransferases (HATs) are important enzymes that transfer acetyl groups onto histones and thereby regulate both gene expression and chromosomal structures. Previous work has shown that the activation of sirtuins, which are histone deacetylases, can extend lifespan. This suggests that inhibiting HATs may have a similar beneficial effect. In the present study, we utilized a range of HAT inhibitors or heterozygous Gcn5 and Ngg1 mutants to demonstrate marked yeast life extension. In human cell lines, HAT inhibitors and selective RNAi‐mediated Gcn5 or Ngg1 knockdown reduced the levels of aging markers and promoted proliferation in senescent cells. Furthermore, this observed lifespan extension was associated with the acetylation of histone H3 rather than that of H4. Specifically, it was dependent upon H3K9Ac and H3K18Ac modifications. We also found that the ability of caloric restriction to prolong lifespan is Gcn5‐, Ngg1‐, H3K9‐, and H3K18‐dependent. Transcriptome analysis revealed that these changes were similar to those associated with heat shock and were inversely correlated with the gene expression profiles of aged yeast and aged worms. Through a bioinformatic analysis, we also found that HAT inhibition activated subtelomeric genes in human cell lines. Together, our results suggest that inhibiting the HAT Gcn5 may be an effective means of increasing longevity.

中文翻译：

组蛋白乙酰基转移酶GCN5的抑制延长了酵母和人类细胞系的寿命。

组蛋白乙酰基转移酶（HATs）是重要的酶，可将乙酰基转移到组蛋白上，从而调节基因表达和染色体结构。先前的研究表明，sirtuins的活化是组蛋白脱乙酰基酶，可以延长寿命。这表明抑制HAT可能具有类似的有益效果。在本研究中，我们利用了一系列HAT抑制剂或杂合Gcn5和Ngg1突变体来证明酵母的寿命显着延长。在人类细胞系中，HAT抑制剂和选择性RNAi介导的Gcn5或Ngg1敲低可降低衰老标记的水平并促进衰老细胞的增殖。此外，观察到的寿命延长与组蛋白H3而不是H4的乙酰化有关。具体来说，它取决于H3K9Ac和H3K18Ac的修饰。我们还发现，热量限制延长寿命的能力取决于Gcn5‐，Ngg1，H3K9‐和H3K18‐。转录组分析显示，这些变化与热休克相关，与衰老的酵母和蠕虫的基因表达谱呈负相关。通过生物信息学分析，我们还发现HAT抑制可激活人细胞系中的亚端粒基因。总之，我们的结果表明，抑制HAT Gcn5可能是延长寿命的有效手段。通过生物信息学分析，我们还发现HAT抑制可激活人细胞系中的亚端粒基因。总之，我们的结果表明，抑制HAT Gcn5可能是延长寿命的有效手段。通过生物信息学分析，我们还发现HAT抑制可激活人细胞系中的亚端粒基因。总之，我们的结果表明，抑制HAT Gcn5可能是延长寿命的有效手段。

更新日期：2020-03-11

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