Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism

Ruofan Yu, Xiaohua Cao, Luyang Sun, Jun-yi Zhu, Brian M Wasko, Wei Liu, Emeline Crutcher, Haiying Liu, Myeong Chan Jo, Lidong Qin, Matt Kaeberlein, Zhe Han and Weiwei Dang ()
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Ruofan Yu: Baylor College of Medicine
Xiaohua Cao: Baylor College of Medicine
Luyang Sun: Baylor College of Medicine
Jun-yi Zhu: University of Maryland School of Medicine
Brian M Wasko: University of Washington
Wei Liu: Baylor College of Medicine
Emeline Crutcher: Baylor College of Medicine
Haiying Liu: Baylor College of Medicine
Myeong Chan Jo: Innovative BioChips
Lidong Qin: Houston Methodist Research Institute
Matt Kaeberlein: University of Washington
Zhe Han: University of Maryland School of Medicine
Weiwei Dang: Baylor College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22257-2

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