Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence.,Molecular Cell

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Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence.
Molecular Cell ( IF 14.5 ) Pub Date : 2020-03-23 , DOI: 10.1016/j.molcel.2020.03.004
Spencer A Haws ₁ , Deyang Yu ₂ , Cunqi Ye ₃ , Coral K Wille ₄ , Long C Nguyen ₅ , Kimberly A Krautkramer ₁ , Jay L Tomasiewicz ₆ , Shany E Yang ₇ , Blake R Miller ₇ , Wallace H Liu ₁ , Kazuhiko Igarashi ₈ , Rupa Sridharan ₉ , Benjamin P Tu ₃ , Vincent L Cryns ₁₀ , Dudley W Lamming ₁₁ , John M Denu ₁

Affiliation

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.
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.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA.
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.
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.
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.
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.

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.

中文翻译：

甲基代谢物消耗引发适应性反应以支持异染色质稳定性和表观遗传持久性。

S-腺苷甲硫氨酸 (SAM) 是 DNA 和组蛋白甲基转移酶的甲基供体底物，可调节表观遗传状态和随后的基因表达。这种代谢-表观基因组联系使染色质甲基化对 SAM 丰度的改变敏感，但在生命经历的 SAM 可用性波动期间，生物体能够适应和保护表观遗传信息的机制尚不清楚。我们发现了对 SAM 耗尽的强烈反应，其突出特点是 H3 Lys 9 (H3K9) 的优先细胞质和核单甲基化，但代价是组蛋白二甲基化和三甲基化的广泛损失。在 SAM 耗尽的条件下，H3K9 单甲基化可保持异染色质稳定性并支持代谢恢复后的整体表观遗传持久性。这种独特的染色质反应在小鼠的整个生命周期中都很强大，并且与代谢健康状况的改善相关，支持表观遗传适应体内 SAM 耗竭的重要作用。总之，这些研究为适应性反应提供了证据，这种反应能够使表观遗传对代谢应激持续存在。

更新日期：2020-03-24

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