Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory

Abstract

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.

De novo acetate production is coupled to central carbon metabolism in mammals

“…4g). The enrichment of 13 (Fig. 4i), indicating that these metabolites were produced locally confirming our findings in vitro and in cultured cells ( Fig.…”

“…Next in tumor-bearing mice, both serum and tumor tissue were collected for metabolite analysis after 3 hrs of glucose infusion. 13 C labeled pyruvate, lactate, acetate and acetaldehyde were detected in tumor tissue at different concentrations (Fig. 4g).…”

“…3d). Surprisingly, in the absence of CoA and NAD + , pyruvate was still consumed by PDH in the presence of TPP, but instead converted to [ 13 Supplementary Fig. 3a), with lower overall PDH activity (Fig.…”

“…The dependence on acetate to supply both nucleocytosolic and mitochondrial acetyl-CoA pools has been identified in multiple cell types, including cancer cells, T cells, and neurons [8][9][10]13,14 . Our study provides evidence for a glucose-derived overflow pathway for acetate metabolism that occurs in mammalian cells.…”

“…Acetate metabolism provides a parallel pathway for acetylcoA production separate from conversion of citrate to acetyl-CoA by ATP citrate lyase (ACLY) and thus acetate allows for protein acetylation and lipogenesis independent of citrate conversation to acetyl-CoA. This pathway is essential in nutrient deprived tumor microenvironments and other diverse contexts but the origin of acetate has been unclear [8][9][10][11][12][13][14] . It has been postulated that acetate may be synthesized de novo in cells [15][16][17][18][19] but the pathways and quantitative reaction mechanisms through which this may occur are unknown.…”