SUMMARY Metabolic production of acetyl-CoA is linked to histone acetylation and gene regulation, yet the precise mechanisms are largely unknown. Here we show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a direct regulator of histone acetylation in neurons and of spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in nuclei of differentiating neurons and localizes to upregulated neuronal genes near elevated histone acetylation. Reduction of 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 reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a unique connection between cellular metabolism, gene regulation, and neural plasticity, establishing a link between acetyl-CoA generation “on-site” at chromatin for histone acetylation and the transcription of critical neuronal genes.

This comprehensive picture of transcriptome-wide regulation in the brain's reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.

Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, implicating specific metabolic factors in neural functions that drive behavior 1 . In neurons, histone acetylation relies on the metabolite acetyl-CoA that is produced from acetate by chromatin-bound acetyl-CoA synthetase 2 (ACSS2) 2 . Notably, a major source of acetate is via breakdown of alcohol in the liver, leading to rapidly increasing blood acetate 3 . Neuronal histone acetylation may thus be under the influence of alcohol-derived acetate 4 , with potential effects on alcohol-induced brain gene expression and behavior 5 . Here, using in vivo stable isotope labeling in mouse, we show that alcohol metabolism contributes to rapid histone acetylation in the brain in part by direct deposition of alcohol-derived acetyl groups onto histones in an ACSS2-dependent manner. A similar induction was observed with heavy labeled acetate injection in vivo. In a pregnant mouse, exposure to labeled alcohol resulted in incorporation of labeled acetyl groups into gestating fetal brains. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced learning and memory-related transcriptional programs that were sensitive to ACSS2 inhibition. Notably, we Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Understanding transcriptional changes engaged in stress resilience may reveal novel antidepressant targets. Here, we use gene co-expression analysis of RNA-sequencing data from brains of resilient mice to identify a gene network that is unique to resilience. Zfp189, which encodes a previously unstudied zinc finger protein, is the highest-ranked key driver gene in the network, and overexpression of Zfp189 in prefrontal cortical (PFC) neurons preferentially activates this network and promotes behavioral resilience. The transcription factor CREB is a predicted upstream regulator of this network and binds to the Zfp189 promoter. To probe CREB- Zfp189 interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189 promoter in PFC neurons. Induction of Zfp189 with site-specific CREB is pro-resilient, whereas suppressing Zfp189 expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189 and CREB- Zfp189 interactions in mediating a central transcriptional network of resilience.

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Cell growth is attuned to nutrient availability to sustain homeostatic biosynthetic processes. In unfavorable environments, cells enter a nonproliferative state termed quiescence but rapidly return to the cell cycle once conditions support energetic needs. Changing cellular metabolite pools are proposed to directly alter the epigenome via histone acetylation. Here we studied the relationship between histone modification dynamics and the dramatic transcriptional changes that occur during nutrient-induced cell cycle reentry from quiescence in the yeast Saccharomyces cerevisiae. SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry showed that histone methylation-in contrast to histone acetylation-is surprisingly static during quiescence exit. Chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) revealed genomewide shifts in histone acetylation at growth and stress genes as cells exit quiescence and transcription dramatically changes. Strikingly, however, the patterns of histone methylation remain intact. We conclude that the functions of histone methylation and acetylation are remarkably distinct during quiescence exit: acetylation rapidly responds to metabolic state, while methylation is independent. Thus, the initial burst of growth gene reactivation emerging from quiescence involves dramatic increases of histone acetylation but not of histone methylation. C ells constantly sense and integrate environmental cues to control proliferative growth, but the underlying molecular mechanisms remain unclear. Eukaryotic cells, including adult stem cells, typically exist in a state of growth arrest-quiescence-that is distinguished by two principal qualities: quiescent cells both safeguard cell identity and retain the ability to resume proliferation once external cues become favorable (1-3). Remarkably little is known about the molecular processes that mediate quiescence exit and the transition to proliferative growth, which requires massive changes in cell metabolism and reprogramming of global gene expression (4-6).Recent evidence suggests that the metabolic state is a principle regulator of quiescence establishment and exit via epigenetic changes that alter gene expression (7-9). A clear example is that nutrient-induced increases in acetyl coenzyme A (acetyl-CoA) pools promote chromatin acetylation and growth gene transcription (10, 11). Rhythmic fluctuations of acetyl-CoA levels are characteristic of the metabolic cycle that budding yeast cells enter during growth under nutrient-limiting conditions. In such a milieu, recurrent bursts of acetyl-CoA production by the acetyl-CoA synthase Acs2p have been linked to increased histone acetylation and growth gene expression, indicating a functional connection between metabolic state and gene transcription via chromatin acetylation (10). Indeed, studies in both the yeast Saccharomyces cerevisiae and activated lymphocytes indicate that glucose-induced histone acetylation is a critical and highly conserved driver of quie...

Drug addiction is a chronic relapsing brain disorder that is characterized by compulsive drug seeking and continued use despite negative outcomes. Current pharmacological therapies target neuronal receptors or transporters upon which drugs of abuse act initially, yet these treatments remain ineffective for most individuals and do not prevent disease relapse after abstinence. Drugs of abuse, in addition to their acute effects, cause persistent plasticity after repeated use, involving dysregulated gene expression in the brain's reward regions, which are thought to mediate the persistent behavioral abnormalities that characterize addiction. Emerging evidence implicates epigenetic priming as a key mechanism that underlies the long-lasting alterations in neuronal gene regulation, which can remain latent until triggered by re-exposure to drug-associated stimuli or the drug itself. Thus, to effectively treat drug addiction, we must identify the precise epigenetic mechanisms that establish and preserve the druginduced pathology of the brain reward circuitry.

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