Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence

Spencer A. Haws; Deyang Yu; Cunqi Ye; Coral K. Wille; Long C. Nguyen; Kimberly A. Krautkramer; Jay L. Tomasiewicz; Shany E. Yang; Blake R. Miller; Wallace H. Liu; Kazuhiko Igarashi; Rupa Sridharan; Benjamin P. Tu; Vincent L. Cryns; Dudley W. Lamming; John M. Denu

doi:10.1101/726448

Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence

Spencer A. Haws, Deyang Yu, Cunqi Ye, Coral K. Wille, Long C. Nguyen, Kimberly A. Krautkramer, Jay L. Tomasiewicz, Shany E. Yang, Blake R. Miller, Wallace H. Liu, Kazuhiko Igarashi, Rupa Sridharan, Benjamin P. Tu, Vincent L. Cryns, Dudley W. Lamming, John M. Denu

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

Abstract

S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate cellular epigenetic states. This metabolism-epigenome link enables the sensitization of chromatin methylation to altered SAM abundance. However, a chromatin-wide understanding of the adaptive/responsive mechanisms that allow cells to actively protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear de novo mono-methylation of H3 Lys 9 (H3K9) at the expense of global losses in histone di- and tri-methylation. Under SAM-depleted conditions, de novo H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide the first evidence for active epigenetic adaptation and persistence to metabolic stress.

Original language	English (US)
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/726448
State	Published - Aug 6 2019

Keywords

aging
chromatin
epigenetics
histone
metabolism
methionine
methylation
persistence
SAM

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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Haws, S. A., Yu, D., Ye, C., Wille, C. K., Nguyen, L. C., Krautkramer, K. A., Tomasiewicz, J. L., Yang, S. E., Miller, B. R., Liu, W. H., Igarashi, K., Sridharan, R., Tu, B. P., Cryns, V. L., Lamming, D. W., & Denu, J. M. (2019). Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence. Unknown Journal. https://doi.org/10.1101/726448

Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence. / Haws, Spencer A.; Yu, Deyang; Ye, Cunqi; Wille, Coral K.; Nguyen, Long C.; Krautkramer, Kimberly A.; Tomasiewicz, Jay L.; Yang, Shany E.; Miller, Blake R.; Liu, Wallace H.; Igarashi, Kazuhiko; Sridharan, Rupa; Tu, Benjamin P.; Cryns, Vincent L.; Lamming, Dudley W.; Denu, John M.

In: Unknown Journal, 06.08.2019.

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

Haws, Spencer A. ; Yu, Deyang ; Ye, Cunqi ; Wille, Coral K. ; Nguyen, Long C. ; Krautkramer, Kimberly A. ; Tomasiewicz, Jay L. ; Yang, Shany E. ; Miller, Blake R. ; Liu, Wallace H. ; Igarashi, Kazuhiko ; Sridharan, Rupa ; Tu, Benjamin P. ; Cryns, Vincent L. ; Lamming, Dudley W. ; Denu, John M. / Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence. In: Unknown Journal. 2019.

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title = "Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence",

abstract = "S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate cellular epigenetic states. This metabolism-epigenome link enables the sensitization of chromatin methylation to altered SAM abundance. However, a chromatin-wide understanding of the adaptive/responsive mechanisms that allow cells to actively protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear de novo mono-methylation of H3 Lys 9 (H3K9) at the expense of global losses in histone di- and tri-methylation. Under SAM-depleted conditions, de novo H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide the first evidence for active epigenetic adaptation and persistence to metabolic stress.",

keywords = "aging, chromatin, epigenetics, histone, metabolism, methionine, methylation, persistence, SAM",

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T1 - Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence

AU - Haws, Spencer A.

AU - Yu, Deyang

AU - Ye, Cunqi

AU - Wille, Coral K.

AU - Nguyen, Long C.

AU - Krautkramer, Kimberly A.

AU - Tomasiewicz, Jay L.

AU - Yang, Shany E.

AU - Miller, Blake R.

AU - Liu, Wallace H.

AU - Igarashi, Kazuhiko

AU - Sridharan, Rupa

AU - Tu, Benjamin P.

AU - Cryns, Vincent L.

AU - Lamming, Dudley W.

AU - Denu, John M.

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2019/8/6

Y1 - 2019/8/6

N2 - S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate cellular epigenetic states. This metabolism-epigenome link enables the sensitization of chromatin methylation to altered SAM abundance. However, a chromatin-wide understanding of the adaptive/responsive mechanisms that allow cells to actively protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear de novo mono-methylation of H3 Lys 9 (H3K9) at the expense of global losses in histone di- and tri-methylation. Under SAM-depleted conditions, de novo H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide the first evidence for active epigenetic adaptation and persistence to metabolic stress.

AB - S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate cellular epigenetic states. This metabolism-epigenome link enables the sensitization of chromatin methylation to altered SAM abundance. However, a chromatin-wide understanding of the adaptive/responsive mechanisms that allow cells to actively protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear de novo mono-methylation of H3 Lys 9 (H3K9) at the expense of global losses in histone di- and tri-methylation. Under SAM-depleted conditions, de novo H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide the first evidence for active epigenetic adaptation and persistence to metabolic stress.

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KW - chromatin

KW - epigenetics

KW - histone

KW - metabolism

KW - methionine

KW - methylation

KW - persistence

KW - SAM

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