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

Mol Cell. 2020 Apr 16;78(2):210-223.e8. doi: 10.1016/j.molcel.2020.03.004. Epub 2020 Mar 23.

Authors

Affiliations

¹ Department of Biomolecular Chemistry, SMPH, University of Wisconsin-Madison, Madison, WI 53706, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
² William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular & Environmental Toxicology Center, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
⁵ Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
⁶ William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
⁷ William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁸ Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
⁹ Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA.
¹⁰ Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular & Environmental Toxicology Center, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA.
¹¹ William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular & Environmental Toxicology Center, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA.
¹² Department of Biomolecular Chemistry, SMPH, University of Wisconsin-Madison, Madison, WI 53706, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Electronic address: john.denu@wisc.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Nucleus / genetics
Cell Nucleus / metabolism
Chromatin / genetics
Cytoplasm / genetics
Cytoplasm / metabolism
DNA Methylation / genetics*
Epigenesis, Genetic / genetics
Gene Expression Regulation / genetics
HCT116 Cells
Heterochromatin / genetics*
Heterochromatin / metabolism
Histone-Lysine N-Methyltransferase / genetics
Histones / genetics
Humans
Metabolome / genetics*
Methionine / genetics
Mice
Protein Processing, Post-Translational / genetics
Proteomics / methods
S-Adenosylmethionine / metabolism*

Substances

Chromatin
Heterochromatin
Histones
S-Adenosylmethionine
Methionine
Histone-Lysine N-Methyltransferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding