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Alcohol metabolism contributes to brain histone acetylation - Coggle…
Alcohol metabolism contributes to brain histone acetylation
Introduction
epigenetic regulation is dependent on metabolic state, and implicates specific metabolic factors in neural functions that drive behaviour
In neurons, acetylation of histones relies on the metabolite acetyl-CoA, which is produced from acetate by chromatin-bound acetyl-CoA synthetase 2 (ACSS2)
the breakdown of alcohol in the liver leads to a rapid increase in levels of blood acetate
Histone acetylation in neurons may thus be under the influence of acetate that is derived from alcohol
potential effects on alcohol-induced gene expression in the brain, and on behaviou
Results
To determine whether acetate that is produced from the breakdown of alcohol contributes to dynamic acetylation of histones in the brain
used in vivo stable-isotope labelling of protein acetylation, monitored by mass spectrometry
Brain
the abundance of labelled acetylated histones was lower in skeletal muscle
Liver
To test whether ACSS2 is required for the incorporation of alcohol-derived acetate into the brain
attenuated the expression of ACSS2 in the dorsal hippocampus (dHPC) by shRNA knockdown using a previously validated viral vector
In these ACSS2-knockdown mice
compared alcohol-derived histone acetylation separately in the dHPC
assessed the contribution of acetyl groups that are derived from extracellular acetate to histone acetylation in the brain
In mice that were intraperitoneally injected with 2 g kg−1 deuterated acetate (acetate-d3)
we detected substantial amounts of heavy acetate in the hippocampus
whether alcohol-derived carbon groups are incorporated into other key metabolites in hippocampal tissue
detected only traces of the alcohol-derived label in pools of citrate or isocitrate in the hippocampus
aken together with our mass spectrometry data in ACSS2-knockdown mice
examined the functional relevance of alcohol-derived acetate for ACSS2-dependent histone acetylation in regulating the expression of genes in the hippocampus.
Evaluating the ChIP–seq data for histone acetylation on a genome-wide scale
ex vivo assay to more closely model the direct effects of exogenous acetate on gene expression
used isolated mouse primary hippocampal neurons
to investigate the transcriptional response to supraphysiological levels of acetate that mimic the influx of exogenous acetate during alcohol intake
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