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.
Mol Cell. 2020 Apr 16;78(2):210-223.e8. doi: 10.1016/j.molcel.2020.03.004. Epub 2020 Mar 23.
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.
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-表观基因组的联系使染色质甲基化对 SAM 丰度的改变敏感，但允许生物体在 SAM 可用性发生生活经历波动时适应和保护表观遗传信息的机制尚不清楚。我们发现了一种对 SAM 耗竭的强烈反应，其特点是 H3 赖氨酸 9（H3K9）的细胞质和核单甲基化优先，而广泛的组蛋白二甲基化和三甲基化损失。在 SAM 耗尽的条件下，H3K9 单甲基化可维持异染色质稳定性，并在代谢恢复后支持全局表观遗传持久性。这种独特的染色质反应在整个小鼠寿命中都很稳健，并与改善的代谢健康相关，支持了表观遗传适应 SAM 耗竭在体内的重要作用。总之，这些研究为适应代谢应激的表观遗传持久性提供了证据。
