Aberrant epigenetic status resulting in dysregulation of gene expression is a hallmark of many cancers and other diseases. In the last decade, countless time and energy has been spent in efforts to develop drugs targeting DNA methylation and histone modifications. To date however, none of these epigenetic drugs are sequence specific: they target epigenome-regulating proteins rather than the DNA itself. Thus, although drug treatment may alleviate symptoms of epigenetic dysregulation at a certain region of DNA, the drug’s genome-wide influence may actually cause dysregulation at other regions.
In contrast, transcription factors are proteins that are able to bind to specific DNA sequences and recruit additional machinery. In efforts to increase the specificity of interactions between epigenetic drugs and their target regions, Artificial Transcription Factors (ATFs) are currently being developed for clinical applications. These ATF proteins can be engineered, in theory, to modulate expression of specific target genes by binding to a specific DNA region and recruiting epigenetic machinery such as TETs, DNMTs, and histone modifying complexes in order to modify the local epigenetic landscape.
A recent study stated that the genome-wide binding patterns and influences of two ATFs that target the SOX2 promoter, which plays a large role in maintaining cell self-renewal and has been implicated in several cancers.
Although ATFs represent an exciting advancement in epigenetic drug development, advancements should be done for better understanding of how zinc fingers work together to bind DNA and how transcription factors may use different subsets to bind different sequences.