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乙酰辅酶A合成酶调节组蛋白乙酰化和海马体记忆。

Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory.

作者信息

Mews Philipp, Donahue Greg, Drake Adam M, Luczak Vincent, Abel Ted, Berger Shelley L

机构信息

Epigenetics Institute, Departments of Cell and Developmental Biology, Biology, Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.

出版信息

Nature. 2017 Jun 15;546(7658):381-386. doi: 10.1038/nature22405. Epub 2017 May 31.

DOI:10.1038/nature22405
PMID:28562591
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5505514/
Abstract

Metabolic production of acetyl coenzyme A (acetyl-CoA) is linked to histone acetylation and gene regulation, but the precise mechanisms of this process are largely unknown. Here we show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) directly regulates histone acetylation in neurons and spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in the nuclei of differentiating neurons and localizes to upregulated neuronal genes near sites of elevated histone acetylation. A decrease in ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of the cohort of neuronal genes. In adult mice, attenuation of hippocampal ACSS2 expression impairs long-term spatial memory, a cognitive process that relies on histone acetylation. A decrease in ACSS2 in the hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a connection between cellular metabolism, gene regulation, and neural plasticity and establish a link between acetyl-CoA generation 'on-site' at chromatin for histone acetylation and the transcription of key neuronal genes.

摘要

乙酰辅酶A（acetyl-CoA）的代谢生成与组蛋白乙酰化及基因调控相关，但这一过程的确切机制在很大程度上尚不清楚。在此，我们表明代谢酶乙酰辅酶A合成酶2（ACSS2）直接调控哺乳动物神经元中的组蛋白乙酰化及空间记忆。在神经元细胞培养模型中，ACSS2在分化神经元的细胞核中增加，并定位于组蛋白乙酰化升高位点附近上调的神经元基因处。ACSS2的减少会降低细胞核中乙酰辅酶A水平、组蛋白乙酰化以及神经元基因群组的反应性表达。在成年小鼠中，海马体ACSS2表达的减弱会损害长期空间记忆，这是一种依赖于组蛋白乙酰化的认知过程。海马体中ACSS2的减少还会导致由ACSS2预先结合的记忆相关神经元基因的上调缺陷。这些结果揭示了细胞代谢、基因调控和神经可塑性之间的联系，并在染色质上用于组蛋白乙酰化的“现场”乙酰辅酶A生成与关键神经元基因的转录之间建立了联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/25b1e9b68451/nihms872465f4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/31dfd534a3f1/nihms872465f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/5cf382b8ee64/nihms872465f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/c181471ebae6/nihms872465f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/181d69ab67ae/nihms872465f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/f86abe92bb7f/nihms872465f11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/c93d264247e2/nihms872465f12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/3397c4a21f92/nihms872465f13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/5c09056efdf4/nihms872465f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de3/5505514/68b82a347478/nihms872465f2.jpg
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