Effects of methyl donors or polyphenols (eg myricetin, EGCG, luteolin, genistein) on DNA methylation/DNMT activity?


Eg luteolin, EGCG. EGCG is supposedly a DNMT inhibitor which could prevent hypermethylation issues caused by too much folate, but the question is does it also inhibit DNMT when spread on “good” regions, such as “green yellow module”

question 2: does DNMT spread more on CpG islands, shores, shelves, or regions of high methylation density vs low methylation density? See Duncan Sproul’s latest paper

Low CpG density shows more variable methylation trajectories - is this affected by DNMT activity?

See Kara Fitzgerald’s book “Younger You”. I know some have critiqued Kara on the methodology (and DNAm test used) of her paper, but her ideas are still worth exploring.
I know Alex Zharovonkov has found myricetin in a screen

Other relevant questions: are oncogenes (and their promoters) more likely to be in low CpG-density or high CpG density regions? are their methylation patterns more likely to be in one module as opposed to another? Hypermethylation of tumor suppressors inhibits them and is something you expect to happen more often with “age/bad things” so it is unlikely that they would be in most of Levine’s modules (like green-yellow)

Green tea has also been shown to modulate DNMT activity to inhibit tumorigenesis. EGCG, the major polyphenol in green tea, has many interesting activities and is believed to be a key active ingredient. It dose-dependently inhibited DNMT activity, showing competitive inhibition with a Ki of 6.89 μM in human esophageal squamous cell carcinoma cell lines (152, 160). Moreover, a breast cancer study demonstrated that tea polyphenols [catechin, epicatechin, and (−)-epigallocatechin-3-O-gallate (EGCG)] and bioflavonoids (quercetin, fisetin, and myricetin) inhibited DNMT1-mediated DNA methylation in a dose dependent manner

Accordingly, methyl donors from the diet are associated with the alteration of methylation status, but there are many uncertainties about doses and the duration of dietary exposure resulting in epigenetic changes of DNA [58]. As described previously, DNMTs require SAM as a cofactor. However, the activity of SAM may be modulated by dietary intervention, leading to the modulation of its concentration in the cell. Moreover, the activity and stability of methyltransferases is inhibited directly and competitively through interaction with natural compounds, including EGCG, a phenolic from green tea, genistein from soybean, or myricetin as the representative of dietary flavonoids

Gah, SAM-e increases homocysteine

BTW, biosynthesis of creatine takes up A LOT of methyl groups which is why supplemental creatine might reduce DNAm age by freeing up methyl donors for other things (hence ALWAYS have a source of supplemental creatine)

Morphoceuticals are a novel class of therapeutics inspired by this perspective, developed to exploit the modular, error-correcting capabilities of tissues instead of trying to micromanage pathways. Here we focus on a subset of these – electroceuticals - that specifically target bioelectric networks using ion channel drugs and other modalities (Figure 2).

So… are there Methylceuticals that let you avoid micromanagement? (mature phase transient reprogramming is a way…)

Wasn’t sure where to post this. I just saw this today and wanted to get feedback from my esteemed colleagues. :grin: Hadn’t heard of this publication before, but it’s a good read.


During aging there is a decrease in global DNA methylation and an increase in local methylation at CpG islands and specific promoters (Jones et al., 2015; Johnson et al., 2012, Sun and Yi, 2015; Pérez et al., 2022).
Hypomethylated CpG sites are strongly enriched in the active histone
mark H3K4me1, and hypermethylated sequences enriched in the repressive
marks H3K27me3/H3K9me3 (Fernández et al., 2015) while expression of the strong repressors miRNAs, which seem to regulate up to 60 % of human protein coding genes (Friedman et al., 2009), also changes during aging (Sierra et al., 2015; Lai et al., 2019).

Does it differentially influence one at expense of the other?


Zebularine a DNA methyltransferase (DNMT) inhibitor, supposedly reduces rate of DNAm aging (but functional significance is unclear). It’s said [w/o super-strong evidence yet] that B12/B6 vitamins help “reduce epigenetic age” and they are on average methyl donors… CpG clock sites are typically positioned at active genes and not in the weird transposons throughout the genome (increasing global DNA methylation is a good thing on average, but not at the CpG islands and specific promoters that are measured by CpG clock sites)

Maybe upon mitosis, methylation state is more likely to be maintained in CpG islands than retrotransposon regions or the opposite, idk