With new tools and techniques to study the sixth base, 5-hydroxymethylcytosine (5-hmC), reports starting to pour in to shed new light on just what the heck it does. Now researchers in the UK have shown that changes in the relative levels of 5mC and 5hmC in embryonic stem (ES) cells could help tip cells toward differentiation; a balancing act that would make the Flying Wallendas jealous.
The team used MeDIP-Seq and hMeDIP-Seq to look at genome-wide patterns of 5mC and 5hmC in mouse ES cells and differentiating embryoid bodies. They found interesting differences in 5mC/5hmC distributions among genomic regions and cell types:
- In contrast to transcriptionally repressive 5mC, 5hmC is mostly associated with euchromatin and regions of active transcription
- Knockdown of Tet1 and Tet2, the enzymes that generate 5hmC from pre-existing 5mC, downregulates pluripotency-related genes, increases their promoter methylation, and drives ES cells toward differentiation
- As ES cells differentiate and TET levels decline, 5hmC in promoters of ES cell-specific genes decreases, while 5mC and gene silencing increase
These data led the researchers to conclude, “The balance between hydroxymethylation and methylation in the genome is inextricably linked with the balance between pluripotency and lineage commitment.” But they don’t know yet whether the transcription-promoting effect of 5hmC is due merely to its removal of the repressive effect of 5mC, or whether 5hmC itself can recruit transcriptional activators.
Get a perfectly balanced take on the facts at Nature, April 2011.