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; Weiwei Dang

doi:10.1038/s41467-021-22257-2

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, Weiwei Dang

Academic Institute

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Article number	1981
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22257-2
State	Published - Dec 1 2021

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-021-22257-2

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title = "Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism",

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.",

author = "Ruofan Yu and Xiaohua Cao and Luyang Sun and Zhu, {Jun yi} and Wasko, {Brian M.} and Wei Liu and Emeline Crutcher and Haiying Liu and Jo, {Myeong Chan} and Lidong Qin and Matt Kaeberlein and Zhe Han and Weiwei Dang",

note = "Funding Information: We thank G. Ira, M. Wang, A. Catic, and A. Bertuch for useful discussion during this study, and P. Gibney for kindly sharing yeast strains. This study is supported by NIH grants R00AG037646, R01AG052507, and R42AG058368, CPRIT award R1306, and Welch Foundation grant Q-1986-20190330 to W.D., NIH grant R01HL134940 to Z.H., the University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging (NIH grant P30AG013280 to M.K.), and Kalman/AFAR Scholarship to R.Y. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-021-22257-2",

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AU - Yu, Ruofan

AU - Cao, Xiaohua

AU - Sun, Luyang

AU - Zhu, Jun yi

AU - Wasko, Brian M.

AU - Liu, Wei

AU - Crutcher, Emeline

AU - Liu, Haiying

AU - Jo, Myeong Chan

AU - Qin, Lidong

AU - Kaeberlein, Matt

AU - Han, Zhe

AU - Dang, Weiwei

N1 - Funding Information: We thank G. Ira, M. Wang, A. Catic, and A. Bertuch for useful discussion during this study, and P. Gibney for kindly sharing yeast strains. This study is supported by NIH grants R00AG037646, R01AG052507, and R42AG058368, CPRIT award R1306, and Welch Foundation grant Q-1986-20190330 to W.D., NIH grant R01HL134940 to Z.H., the University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging (NIH grant P30AG013280 to M.K.), and Kalman/AFAR Scholarship to R.Y. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

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Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism

Abstract

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