If the field of epigenetics is heading into adolescence (rapid growth, disruptive, with occasional data tantrums), the arena of Epigenetic Editing (gene-specific rewriting of epigenetic marks) is more zygotic than anything, with far more questions than answers. But the concept of systematically manipulating epigenetic marks to modulate gene expression is injecting some air back into the gene therapy balloon that has deflated a bit over the years.
A few of our friends in the Netherlands led by Dr. Marianne Rots published a nice review last week that summarizes the state of genome editing and how these advances are currently being applied to Epigenetic Editing.
The promise of Epigenetic Editing is summarized nicely in a table that illustrates the targeted effector domains and their effects. Interestingly, for certain enzymes, the data strongly indicate that it indeed is the induced mark, which provokes the gene expression modulation.
However, for others, the observed effect on gene expression is likely caused by indirect recruitment of other players. As active overwriting of epigenetic marks might provide a powerful tool to affect gene expression in a mitotically stable way, insights from these summarized targeting studies are expected to help navigate future Epigenetic Editing efforts in the right direction. Here some of the key points and highlights:
- Targeting epigenetic enzymes (domains) to specific chromatin contexts is uniquely suited to provide insights in functions of enzymes and their marks in controlling gene expression
- Targeting catalytic domains (and their catalytically dead counterparts) resulted in the induction of the intended edited mark AND in gene expression modulation for several epigenetic enzymes, but not for their mutants (including Dnmt3a, Dnmt3b, Meisetz, dAsh1, vSET, Suv39H1 and G9A); this indicates a causative role of epigenetic marks in controlling gene expression
- Targeting other domains merely modulates gene expression through recruitment of other activating or repressive proteins
- Epigenetic Editing has successfully been performed for three endogenous genes now (VEGF-A, maspin, sox2) and provides an unique tool to fully exploit the drugability of the complete human genome
Check out the free review at Nucleic Acids Research (Sept 2012)
Also, for more on the first endogenous genes being repressed by targeted DNA methylation, check out: Epigenetic reprogramming of cancer cells via targeted DNA methylation. Epigenetics (2012)