The Development of Targeted DNA Methylation Editing
Given the ability edit genes, why not also work on the ability to edit the epigenetic decorations such as DNA methylation, those that control the rate of gene expression, the production of proteins from the genetic blueprint? All cellular behavior is governed by the pace of production of specific proteins - these are the switches and dials of the cellular machine. So there are countless ways in which such an editing capability might prove useful. Perhaps the most interesting for this community is that efficient epigenetic editing should enable the production of compelling tests to disprove programmed aging theories that claim changes in gene expression to be the root cause of aging. Given that aging looks to be caused instead by accumulating molecular damage, with gene expression changes as a downstream reaction to that damage and its consequences, adjustments to gene expression should be of only marginal benefit, just like most of today's drug-based medicine for age-related disease. The ability to directly and precisely edit gene expression on a gene by gene basis without the use of a drug and its side-effects should make that very clear.
Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing.
Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.
This seems to mean a revolution for cell therapy and tissue engineering.