While Apple seems focused on reducing complexity, the epigenome just can’t stop increasing it. Researchers from the Ludwig-Maximilians-University in Munich have shown that Tet enzymes oxidize not only the methyl group of methyl-cytosine (mC) but also thymine (T).
An analog to the traditional oxidation of 5mC to 5hydroxymethyl-cytosine (5hmC), this case generates hydroxymethyl-uracil (5hmU). By tracing metabolically stable isotopes (incorporated into the genomic DNA of mouse ES stem cells) the team found:
- 5hmU is more abundant in mouse ES cells relative to differentiated tissues.
- This includes the brain where 5hmC is at higher levels than in ES cells.
- Tet1 and Tet2 enzymatically oxidize T to 5hmU.
- 5hmU levels show distinct kinetics during priming of naïve mouse ES cells.
A Regulatory Role for 5hmU
Senior author Fabio Spada shares that “Deamination of 5hmC to 5hmU occurs at such low rates and/or the resulting hmU:G mismatches are so efficiently repaired that hmU deamination does not contribute to the steady state levels of hmU in mouse ES cells.”
This suggests to Spada that the “The 5hmU:A and 5hmC:G base pairs (as well as the 5hmU:G mismatch) share some binding proteins. The presence of 5hmU:A binders hints at a role for Tet-generated 5hmU in transcriptional control and chromatin remodelling. The biological relevance of T oxidation by Tet enzymes is now a major question. We now have further indications that Tet-dependant generation of 5hmU is tightly regulated and not just a byproduct of spurious Tet activity”.
Spada concludes with his groups observation that the “genomic incorporation of 5hmU by direct feeding is highly toxic to cells and we confirmed it for ES cells. As 5hmU is incorporated in place of T it should not be mutagenic, so its toxicity is likely related to some other function. Due to the relatively low abundance of 5hmU and its similarity to 5hmC, the mystery of its role will not be an easy one to crack.”
Learn more about Tet’s hidden love affairs in Nature Chemical Biology, June 2014