Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence
Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence
复制标题
DOI：
10.1016/j.molcel.2020.03.004
复制
发表时间：
2020-04-16
期刊：
影响因子：
16
通讯作者：
Denu, John M.
中科院分区：
文献类型：
--
作者：
Haws, Spencer A.;Yu, Deyang;Denu, John M.
S-腺苷甲硫氨酸是DNA和组蛋白甲基转移酶的甲基供体底物，调节表观遗传状态和随后的基因表达。这种代谢-表观基因组连接使染色质甲基化对SAM丰度的变化敏感，然而，在SAM可获得性的生命经历波动期间，同种异体组织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耗竭的强烈反应，突出表现为H3Lys 9(H3K9)的优先细胞质和核单甲基化，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单甲基化保持了异染色质的稳定性，并支持代谢恢复时的全球表观遗传持久性。这种独特的染色质反应在小鼠的整个寿命中都很强劲，并与代谢健康的改善相关，支持了体内对SAM耗竭的表观遗传适应的重要作用。总之，这些研究提供了证据，证明了一种适应性反应，使表观遗传对代谢应激具有持久性。
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 alloworganisms 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 cyto-plasmic and nuclear mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone diand 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.