TET family proteins grabbed a bit of fame back in 2009 for their role in the demethylation pathway that generates one of our favorite base modifcations 5hmC. Since then, researchers have sought out ways to harness TET’s tremendous potential as a mechanism for active regulation of DNA methylation…if only Miley had followed in its’ footsteps. Controlling the expression of your gene of interest with a targeted epigenetic modifier has long been a dream of many. So a cunning team lead by Dr. Marianne Rots (University Medical Center Groningen, The Netherlands) used fusions of designer DNA binding domains and the TET family (1, 2, 3) to target epigenetically silenced genes (ICAM-1, EpCAM).

The EpiGenie team reached out to Dr. Rots for some additional insights on the latest breakthroughs. She shared that while “Aberrant DNA methylation profiles are associated with various diseases…”, therapeutic re-expression of genes can be achieved by epigenetic drugs, although such approaches suffer from “non-chromatin and genome-wide effects”. So in order to fully exploit the reversibility of epigenetic mutations (while limiting off-target effects), Epigenetic Editing has emerged as a powerful new way to modulate gene expression. In Epigenetic Editing, which Rots has been a long-standing advocate for, designer DNA binding domains are fused to epigenetic writers (or erasers) to overwrite the current epigenetic signature.

Here’s what the team found:

Their construct was found to induce demethylation of targeted CpG sites in gene promoters using a TET2 based construct (which also worked to a lesser extent for TET1, but intriguingly not for TET3).

This demethylation was followed by re-activation of transcription in the target gene of interest (ICAM-1),which the Tet fusion was engineered for.

Ultimately, it appears that we now have a novel way to actively target DNA demethylation to a gene of interest and subsequently reactivate expression of the desired target gene.

Epigenetic Editing is an emerging new tool to investigate functions of epigenetic writers and erasers while also teaching us a thing or two about the consequences of epigenetic marks. Rots concludes that, “As conventional approaches to induce DNA demethylation have genome-wide effects, the approach of Epigenetic Editing provides new avenues to specifically re-express endogenous silenced genes. Providing that the issue of specificity is addressed sufficiently, Epigenetic Editing will allow the full exploitation of the druggable genome concept.”

Induce your epigenome over at Nucleic Acids Research, November 2013