美国宾夕法尼亚大学S. L. Berger和G. Egervari等研究人员发现酒精代谢促进大脑组蛋白乙酰化。相关论文于2019年10月23日在线发表于国际学术期刊《自然》。
通过使用小鼠体内的稳定同位素标记，研究人员表明酒精的代谢有助于大脑中组蛋白的快速乙酰化，并且这部分是通过将醇来源的乙酰基（以一种依赖于乙酰辅酶A合成酶2，即ACSS2，的方式）直接沉积到组蛋白中而发生的。当在体内给小鼠注射重标记的乙酸盐时，观察到类似的直接沉积。在怀孕的小鼠中，暴露于标记的酒精会导致标记的乙酰基结合到妊娠胎儿的大脑中。在离体的原代海马神经元中，细胞外乙酸能够诱导与学习和记忆有关的转录程序，这些程序对ACSS2抑制敏感。
研究人员发现酒精相关的联想学习需要体内ACSS2。这些发现表明，酒精代谢和基因调控之间存在直接联系，这是通过大脑中组蛋白的ACSS2依赖性乙酰化来实现的。
新兴的证据表明，表观遗传调控取决于代谢状态，并且在驱动行为的神经功能中牵涉特定的代谢因子。在神经元中，组蛋白的乙酰化依赖于代谢物乙酰辅酶A，它是由染色质结合的ACSS2从乙酸盐产生的。值得注意的是，肝脏中酒精的分解会导致血液中醋酸盐水平的快速增加，因此酒精是体内醋酸盐的主要来源。因此，神经元中的组蛋白乙酰化可能受到源自酒精的乙酸盐的影响，对酒精诱导的大脑中基因表达和行为产生潜在影响。
附：英文原文
Title: Alcohol metabolism contributes to brain histone acetylation
Author: P. Mews, G. Egervari, R. Nativio, S. Sidoli, G. Donahue, S. I. Lombroso, D. C. Alexander, S. L. Riesche, E. A. Heller, E. J. Nestler, B. A. Garcia, S. L. Berger
Issue&Volume: 2019-10-23
Abstract: Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, and implicates specific metabolic factors in neural functions that drive behaviour1. In neurons, acetylation of histones relies on the metabolite acetyl-CoA, which is produced from acetate by chromatin-bound acetyl-CoA synthetase 2 (ACSS2)2. Notably, the breakdown of alcohol in the liver leads to a rapid increase in levels of blood acetate3, and alcohol is therefore a major source of acetate in the body. Histone acetylation in neurons may thus be under the influence of acetate that is derived from alcohol4, with potential effects on alcohol-induced gene expression in the brain, and on behaviour5. Here, using in vivo stable-isotope labelling in mice, we show that the metabolism of alcohol contributes to rapid acetylation of histones in the brain, and that this occurs in part through the direct deposition of acetyl groups that are derived from alcohol onto histones in an ACSS2-dependent manner. A similar direct deposition was observed when mice were injected with heavy-labelled acetate in vivo. In a pregnant mouse, exposure to labelled alcohol resulted in the incorporation of labelled acetyl groups into gestating fetal brains. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced transcriptional programs related to learning and memory, which were sensitive to ACSS2 inhibition. We show that alcohol-related associative learning requires ACSS2 in vivo. These findings suggest that there is a direct link between alcohol metabolism and gene regulation, through the ACSS2-dependent acetylation of histones in the brain.
DOI: 10.1038/s41586-019-1700-7
Source: https://www.nature.com/articles/s41586-019-1700-7
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
