We’ve seen that mitochondria can modify nuclear DNA methylation, but until recently, the identities of the masterminds behind how the powerhouse of the cell can affect epigenetic change in the nucleus have remained classified. Although Stat3 is most notably recruited by LIF to activate the pluripotency gene network in the nucleus, we also know that LIF commands Stat3 to regulate a metabolic control task force in the mitochondria. Now, breaking news has surfaced about the metabolic control of DNA methylation in naive pluripotent cells via LIF-Stat3 mitochondria-epigenetic interplay.
Graziano Martello’s squad (University of Padova, Italy) exposed how metabolic control is linked to genomic DNA hypomethylation of mouse naive pluripotent cells, a requirement for creating an epigenetic blank canvas for developmental plasticity. Squad leader Riccardo M. Betto identified alpha-ketoglutarate (known aliases: αKG and AKG), a metabolite of glutamine, as the messenger between Stat3-mediated metabolism in the mitochondria and DNA methyltransferase activity in the nucleus. Here’s their situation report:
- Dnmt3a and Dnmt3b double knock-out cells are hypomethylated in 98.9% of the same genomic regions as naïve pluripotent cells (in 2iLIF media)
- Knocking out Stat3 causes higher genomic methylation in 376 303 sites and overexpression of Dnmt3a and Dnmt3b
- Hypermethylation is observed in 3.6% of promoters, 36.5% of enhancers, and 83.3% of imprinted DMRs analyzed
- 20.7% of hypermethylated promoter-associated genes are downregulated
- 37% of imprinted genes and 20.5% of hypermethylated enhancer-associated genes are either up- or downregulated, corresponding with their respective regulatory mechanisms
- However, Stat3 does not directly downregulate Dnmt3a and Dnmt3b expression; DNA hypomethylation in naive pluripotent cells is in fact controlled by mitochondrial metabolism downstream of Stat3
- Stat3 induces high αKG levels via glutamine reductive metabolism in the TCA cycle
- Then, αKG downregulates the expression of Otx2, the transcriptional activator of Dnmt3a and Dnmt3b
- Importantly, regulation of Dnmt activity and imprinted transcripts by Stat3 is also evident in vivo as seen in early mouse embryos
When our bodies are under attack by a disease like cancer, even the almighty Stat3 becomes vulnerable; It overreacts and wreaks havoc all around. In many forms of cancer, you will also see DNA methylation taking a hit. Now that intelligence on Stat3-mediated metabolic control of DNA methylation has been uncovered, it could be used to develop defense strategies against cancerous enemies.
Get access to all the intel in Nature Genetics, February 2021.