Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism

• Published in: Nature communications Vol. 12; no. 1; p. 1981
• Main Authors: Yu, Ruofan, Cao, Xiaohua, Sun, Luyang, Zhu, Jun-yi, Wasko, Brian M, Liu, Wei, Crutcher, Emeline, Liu, Haiying, Jo, Myeong Chan, Qin, Lidong, Kaeberlein, Matt, Han, Zhe, Dang, Weiwei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-03-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/62; 38/91; 49/15; 49/39; 49/47; 631/136/7; 631/337/176; 631/80/458/1275; 631/80/86/2366; 64; Acetylation; Aging; Aging - genetics; Animals; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Carbohydrates; Deactivation; Deoxyribonucleic acid; DNA; DNA damage; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Enzyme Activation - genetics; Epigenetics; Gene silencing; Histone deacetylase; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones; Homology; Humanities and Social Sciences; Inactivation; Kinases; Life span; Longevity; Longevity - genetics; Metabolic pathways; Metabolic rate; Metabolism; multidisciplinary; Next-generation sequencing; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Science; Science (multidisciplinary); Stresses; Transcription activation; Trehalose; Trehalose - metabolism; Yeast; Yeasts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22257-2

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.
Histone acetylations are important epigenetic marks for transcriptional activation and respond to metabolic changes. Here the authors develop a lifespan screen and show that inactivation of the histone deacetylase complex activates longevity and protects against stress via trehalose metabolism.