Abstract
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.
Highlights
This increase in lifespan is achieved via disrupting H3 acetylation that is dependent upon Gcn5 and the linked protein Ngg1
We found that the Histone acetyltransferases (HATs) inhibitors epigallocatechin gallate (EGCG)(Choi et al, 2009), anacardic acid (AA), garcinol (GA), and curcumin all prolonged the replicative lifespan of these cells by >50%, 50%, 33%, and 29%, respectively (Figure 1a,b)
We further found that Caloric restriction (CR)-associated lifespan extension was abolished in H3K9A and H3K18A cells, but not in H3K14A mutants (Figure 4e–g), consistent with CR acting through GCN5 and disrupting H3K9/K18 acetylation in order to extend longevity
Summary
Aging is a process in which an organism suffers from a rising risk of death accompanied by a progressive decline in functional and physiological integrity (Lopez-Otin, Blasco, Partridge, Serrano, & Kroemer, 2013). We offer novel evidence indicating that the partial inhibition of specific HATs can mediate the rejuvenation of yeast and human cell lines This increase in lifespan is achieved via disrupting H3 acetylation that is dependent upon Gcn and the linked protein Ngg. We found that EGCG treatment was associated with reduced overall Ac-lysine levels (Figure 1f), with a preferential impact on Ac-H3 relative to Ac-H4 expression (Figure 1f) These results indicate that HAT inhibition can mediate a substantial increase in yeast lifespan in a manner potentially linked to H3 histone acetylation. In H3K14A, H3K14R, and H3K14Q mutants, EGCG still mediated lifespan extension (Figure 3h) Together, these results suggest that both H3K9 and H3K18 acetylation are key targets of Gcn and Ngg, thereby controlling the replicative lifespan of yeast. Our results suggest that HAT inhibition alters the expression of subtelomeric genes, leading to the rejuvenation and lifespan extension of senescent cells
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