That wacky TET enzyme family is at again, but rather than being caught in some compromising positions with DNA or cheating on Cytosine; this time our favorite enzyme family is slacking off, or as they call it ‘working smart’ and splitting up important active DNA demethylation work. Researchers at the Mayo Clinic provide novel insight into how the TET enzymes divide their DNA demethylation labor to establish regular methylation patterns during development and famous cellular transformations, like cancer.

Utilizing siRNA to deplete the TET protein family (TET1, TET2, and TET3) the team shows us an ever so important role in genome-wide 5mC, 5hmC, and transcriptional patterns in a cancer stem cell line. Here’s the whole family story:

All members prevent hypermethylation throughout the genome, particularly in CpG island shores, where TET depletion results in “prolific” hypermethylation.

Without TET1 there is a widespread ‘omic’ depletion of 5hmC.

Removing TET2 and TET3 only depletes 5hmC in a subset of TET1’s targets, suggesting some familial codependence in DNA demthylation.

But showing off their individuality, TET2 and TET3 cause an increase in 5hmC when depleted.

Interestingly, there are some pretty cool effects from chromatin environment, with 5hmC maintenance by them TETs occurring at polycomb-marked chromatin. Adding a final twist to the drama, TET showed it’s preference for 5hmC removal at discrete loci, with highly transcribed genes enriched for H3K4me3 and H3K36me3, although TET2 shows the biggest preference. Overall, these chromatin dynamics reveal some specific roles for the TET enzyme individuals, like TET2, who is also required to for 5hmC enrichment at enhancers. The results of this report identify some important similarities between the TET family and more importantly their differences when it comes to DNA demethylation.

Learn about how the TET family likes to divide their dirty work in Genome Biology, July 2014