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:10.1016/j.molcel.2020.03.004

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

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39 Scopus citations

Abstract

S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and 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 mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, 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 evidence for an adaptive response that enables epigenetic persistence to metabolic stress.

Original language	English (US)
Pages (from-to)	210-223.e8
Journal	Molecular cell
Volume	78
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2020.03.004
State	Published - Apr 16 2020

Keywords

SAM
aging
chromatin
epigenetics
histone
metabolism
methionine
methylation
persistence

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2020.03.004

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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. (2020). Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence. Molecular cell, 78(2), 210-223.e8. https://doi.org/10.1016/j.molcel.2020.03.004

Haws, SA, Yu, D, Ye, C, Wille, CK, Nguyen, LC, Krautkramer, KA, Tomasiewicz, JL, Yang, SE, Miller, BR, Liu, WH, Igarashi, K, Sridharan, R, Tu, BP, Cryns, VL, Lamming, DW & Denu, JM 2020, 'Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence', Molecular cell, vol. 78, no. 2, pp. 210-223.e8. https://doi.org/10.1016/j.molcel.2020.03.004

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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 epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and 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 mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, 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 evidence for an adaptive response that enables epigenetic persistence to metabolic stress.",

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

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

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doi = "10.1016/j.molcel.2020.03.004",

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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.

PY - 2020/4/16

Y1 - 2020/4/16

N2 - S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and 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 mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, 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 evidence for an adaptive response that enables epigenetic persistence to metabolic stress.

AB - S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and 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 mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, 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 evidence for an adaptive response that enables epigenetic persistence to metabolic stress.

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KW - chromatin

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KW - metabolism

KW - methionine

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KW - persistence

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

Abstract

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