Synthetic transcription factor overrides persistent repressive chromatin marks [ChIP-seq]

The prevailing paradigms of epigenetic control posit that signature patterns of post-translational marks on histones guide specific transcriptional outcomes. Methylation of lysine-9 residue of histone H3 (H3K9me3) is implicated in transcriptional silencing through chromatin condensation by its reader HP-1 proteins. Erosion, erasure and subsequent replacement of H3K9me3 by active acetyl-lysine marks accompanies transcriptional up-regulation. Here, we report that a synthetic transcription elongation factor (SynTEF1), selectively targets the disease-causing GAA repeat expansion in frataxin and stimulates gene expression without erasure of the signature repressive marks or removal of HP1 proteins. Added epigenetic perturbation with a pharmacological agent leads to supra-synergistic frataxin expression that is unexpectedly accompanied by a dramatic rise in H3K9me3 levels. Active placement of the signature repressive mark is readily overridden by SynTEF1, demonstrating the fluidity and context-dependence of these marks in regulating gene expression. While forcing a reconsideration of how signature epigenetic marks are interpreted, our results provide key insights for therapeutic intervention in rationally reconfiguring disease-associated epigenetic states.