Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism

Ruofan Yu,Myeong Chan Jo,Lidong Qin,Haiying Liu,Matt Kaeberlein,Luyang Sun,Weiwei Dang,Zhe Han,Brian M Wasko,Xiaohua Cao,Jun-Yi Zhu,Emeline Crutcher,Wei Liu

doi:10.1038/s41467-021-22257-2

Abstract

Histone acetylations are important epigenetic markers for transcriptional activation in response to metabolic changes and various stresses. Using the high-throughput SEquencing-Based Yeast replicative Lifespan screen method and the yeast knockout collection, we demonstrate that the HDA complex, a class-II histone deacetylase (HDAC), regulates aging through its target of acetylated H3K18 at storage carbohydrate genes. We find that, in addition to longer lifespan, disruption of HDA results in resistance to DNA damage and osmotic stresses. We show that these effects are due to increased promoter H3K18 acetylation and transcriptional activation in the trehalose metabolic pathway in the absence of HDA. Furthermore, we determine that the longevity effect of HDA is independent of the Cyc8-Tup1 repressor complex known to interact with HDA and coordinate transcriptional repression. Silencing the HDA homologs in C. elegans and Drosophila increases their lifespan and delays aging-associated physical declines in adult flies. Hence, we demonstrate that this HDAC controls an evolutionarily conserved longevity pathway.

Highlights

Histone acetylations are important epigenetic markers for transcriptional activation in response to metabolic changes and various stresses
In this study, we developed a barcode sequencing-based technique, SEBYL, to perform high-throughput screening for yeast mutants with an altered replicative lifespan (RLS)
We demonstrated that SEBYL yielded results that are consistent with classical experiments, yet taking

Summary

Introduction

Histone acetylations are important epigenetic markers for transcriptional activation in response to metabolic changes and various stresses. Using the high-throughput SEquencingBased Yeast replicative Lifespan screen method and the yeast knockout collection, we demonstrate that the HDA complex, a class-II histone deacetylase (HDAC), regulates aging through its target of acetylated H3K18 at storage carbohydrate genes. The High-Life technique is based on mother cell enrichment and flowcytometry[13]; due to special requirements of the yeast genotype during mother cell enrichment, this method is more suitable for discovering lifespan-affecting chemical compounds in a limited number of yeast strain genotypes Another screening method developed by Sen et al utilized old cell sorting techniques and an oligonucleotide chip array of a barcoded histone mutant collection; the method provided no statistical comparison with traditional low-throughput methods, and the barcode microarray did not have a dynamic range or throughput comparable to sequencing[14]. SEBYL is a robust method that saves time and energy and can discover aging regulating genes using various preexisting yeast mutant collection resources

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