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

63 Pages Posted: 7 Jan 2019 Sneak Peek Status: Review Complete

See all articles by Spencer A. Haws

Spencer A. Haws

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Deyang Yu

University of Wisconsin - Madison - Department of Medicine

Cunqi Ye

University of Texas at Dallas - Department of Biochemistry

Long N. Chen

Tohoku University - Department of Biochemistry

Kimberly A. Krautkramer

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Jay L. Tomasiewicz

University of Wisconsin - Madison - Department of Medicine

Shany E. Yang

University of Wisconsin - Madison - Department of Medicine

Blake R. Miller

University of Wisconsin - Madison - Department of Medicine

Wallace H. Liu

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Kazuhiko Igarashi

Tohoku University - Department of Biochemistry

Benjamin P. Tu

University of Texas at Dallas - Department of Biochemistry

Vincent L. Cryns

University of Wisconsin - Madison - Department of Medicine

Dudley W. Lamming

University of Wisconsin - Madison - Department of Medicine

John M. Denu

University of Wisconsin - Madison - Department of Biomolecular Chemistry

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Abstract

S-adenosylmethionine (SAM) is the methyl-donor cofactor for the DNA and histone methyltransferases that regulate cellular epigenetic states; however, the adaptive mechanisms that allow cells to actively respond to – and recover their functional epigenomes from – perturbations in SAM availability are unknown. Here, we identify an evolutionarily conserved response to SAM depletion that is highlighted by preferential mono-methylation of H3 Lys 9 (H3K9me1) at the expense of global losses in histone di- and tri-methylation. These coordinated pathways drive de novo cytoplasmic and nuclear mono-methylation of H3K9 to preserve heterochromatin stability and support global epigenetic persistence upon metabolic recovery. Furthermore, the dynamic chromatin response at H3K9 to diet-induced SAM deficiency and subsequent metabolic recovery was robust in both young and old C57BL/6J mice, coinciding with whole animal changes in energy metabolism. Together, these studies are the first to reveal active mechanisms for epigenetic adaptation and persistence in response to metabolic stress.

Keywords: metabolism, methionine, SAM, epigenetics, methylation, chromatin, histone, aging, persistence

Suggested Citation

Haws, Spencer A. and Yu, Deyang and Ye, Cunqi and Chen, Long N. and Krautkramer, Kimberly A. and Tomasiewicz, Jay L. and Yang, Shany E. and Miller, Blake R. and Liu, Wallace H. and Igarashi, Kazuhiko and Tu, Benjamin P. and Cryns, Vincent L. and Lamming, Dudley W. and Denu, John M., Methyl-Metabolite Depletion Elicits Coordinated Responses to Support Heterochromatin Stability and Epigenetic Persistence (December 4, 2018). Available at SSRN: https://ssrn.com/abstract=3295644 or http://dx.doi.org/10.2139/ssrn.3295644
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Spencer A. Haws

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Deyang Yu

University of Wisconsin - Madison - Department of Medicine

716 Langdon Street
Madison, WI 53706-1481
United States

Cunqi Ye

University of Texas at Dallas - Department of Biochemistry

2601 North Floyd Road
Richardson, TX 75083
United States

Long N. Chen

Tohoku University - Department of Biochemistry

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Kimberly A. Krautkramer

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Jay L. Tomasiewicz

University of Wisconsin - Madison - Department of Medicine

716 Langdon Street
Madison, WI 53706-1481
United States

Shany E. Yang

University of Wisconsin - Madison - Department of Medicine

716 Langdon Street
Madison, WI 53706-1481
United States

Blake R. Miller

University of Wisconsin - Madison - Department of Medicine

716 Langdon Street
Madison, WI 53706-1481
United States

Wallace H. Liu

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Kazuhiko Igarashi

Tohoku University - Department of Biochemistry

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Benjamin P. Tu

University of Texas at Dallas - Department of Biochemistry

2601 North Floyd Road
Richardson, TX 75083
United States

Vincent L. Cryns

University of Wisconsin - Madison - Department of Medicine

716 Langdon Street
Madison, WI 53706-1481
United States

Dudley W. Lamming

University of Wisconsin - Madison - Department of Medicine

716 Langdon Street
Madison, WI 53706-1481
United States

John M. Denu (Contact Author)

University of Wisconsin - Madison - Department of Biomolecular Chemistry ( email )

United States

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