The reason acetylation is key is that it occurs as part of the RNA Polymerase II complex. AIUI it is a very basic energy availability control on transcription. There is I think a crosstalk between transcription and DNA methylation as well which means that if transcription successfully occurs demethylation occurs.
I think one of the key questions is what happens when RNA Pol II is stalled at a particular point awaiting acetylation and the histone in the neighbourhood is deacetylated.
ACSS2 is interesting because of the acetate metabolism and it may also feed into the effects of things like cider vinegar and alcohol metabolism. However, ACLY and the relationship between SLC25A1 and nuclear acetyl-CoA seem to be the key pathways involved in affecting transcription changes and particularly those which are part of aging.
AIUI ACCS2 is inhibited by acetylation levels so that it tends not to generate acetyl-CoA when the histone is highly acetylated.
The other histone modifications will have some effects and I am sure they are important in some circumstances, but the process of acetylation and deacetylation clearly rests at the centre of transcription control.
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Alcohol increases histone acetylation
As does valproic acid
And acetate supplemenation - Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation | Journal of Neuroinflammation | Full Text [including vinegar]
Several previous studies have demonstrated that acute ethanol has the ability to activate histone acetyltransferases (HATs) and inhibit histone deacetylases (HDACs) in the brain (Pandey et al., 2017; Figure 1). These properties may lead to increased histone acetylation (active epigenetic marks) that produces chromatin remodeling and changes in gene expression in the amygdala, a brain region responsible for comorbidity of anxiety and AUD (Pandey et al., 2008, 2017). Previous research has demonstrated that different alcohols and their metabolites can also induce changes to histone acetylation in hepatocytes (Choudhury and Shukla, 2008).
and “drugs”/psychedelics (incl possibly DOI, still need to see the paper more)
https://www.nature.com/articles/s41380-024-02439-2
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Actually looking at the paper it says ethanol has a direct effect. I have tended to think the effect is via acetate.
I will spent some time on this chasing down the original papers. Ethanol is complicated because its first metabolite (acetaldehyde) is really nasty, but the second one (acetate) is quite helpful.
