Integrated -omics approach reveals persistent DNA damage rewires lipid metabolism and histone hyperacetylation via MYS-1/Tip60.
Integrated -omics approach reveals persistent DNA damage rewires lipid metabolism and histone hyperacetylation via MYS-1/Tip60.
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DOI：
10.1126/sciadv.abl6083
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发表时间：
2022-02-18
期刊：
影响因子：
13.6
通讯作者：
Gurkar AU
中科院分区：
文献类型：
--
作者：
Hamsanathan S;Anthonymuthu T;Han S;Shinglot H;Siefken E;Sims A;Sen P;Pepper HL;Snyder NW;Bayir H;Kagan V;Gurkar AU
尽管DNA损伤与代谢有着复杂的联系，但对DNA损伤所引起的代谢变化却知之甚少。我们使用秀丽隐杆线虫ERCC1-XPF的DNA修复缺陷模型来深入了解基因毒性应激如何驱动衰老。使用多组学方法，我们发现核DNA损伤促进线粒体β氧化并驱动脂肪库的全球损失。这种向β-氧化的代谢转变产生乙酰辅酶A，促进组蛋白超乙酰化和免疫效应因子和细胞色素基因表达的相关变化。我们确定了组蛋白乙酰转移酶my1，作为代谢-表观遗传轴的关键调节因子。我们发现，在DNA损伤的反应中，多不饱和脂肪酸，特别是花生四烯酸（AA）和AA相关的脂质介质升高，这依赖于my -1。总之，这些发现揭示了DNA损伤会改变代谢-表观遗传轴，从而驱动一种类似免疫的反应，从而促进与年龄相关的衰退。持续的DNA损伤会改变代谢-表观遗传轴，从而驱动炎症信号并促进生物衰老。
Although DNA damage is intricately linked to metabolism, the metabolic alterations that occur in response to DNA damage are not well understood. We use a DNA repair–deficient model of ERCC1-XPF in Caenorhabditis elegans to gain insights on how genotoxic stress drives aging. Using multi-omic approach, we discover that nuclear DNA damage promotes mitochondrial β-oxidation and drives a global loss of fat depots. This metabolic shift to β-oxidation generates acetyl–coenzyme A to promote histone hyperacetylation and an associated change in expression of immune-effector and cytochrome genes. We identify the histone acetyltransferase MYS-1, as a critical regulator of this metabolic-epigenetic axis. We show that in response to DNA damage, polyunsaturated fatty acids, especially arachidonic acid (AA) and AA-related lipid mediators, are elevated and this is dependent on mys-1. Together, these findings reveal that DNA damage alters the metabolic-epigenetic axis to drive an immune-like response that can promote age-associated decline. Persistent DNA damage alters the metabolic-epigenetic axis to drive an inflammatory signature and promote biological aging.
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