Expanded CAG/CTG Repeats Resist Gene Silencing Mediated by Targeted Epigenome Editing

Abstract

Epigenome editing is an attractive way to manipulate gene expression. However, editing efficiencies depend on the DNA sequence context in a manner that remains poorly understood.Here we developed a novel system in which any protein can be recruited at will to a GFP reporter.We named it ParB/ANCHOR-mediated Inducible Targeting (PInT). Using PInT, we tested how CAG/CTG repeat size affects the ability of histone deacetylases to modulate gene expression. We found that repeat expansion reduces the effectiveness of silencing brought about by HDAC5targeting. This repeat-length specificity was abolished when we inhibited HDAC3 activity. Our data guide the use of these histone deacetylases in manipulating chromatin. PInT can be adapted to study the effect of virtually any sequence on epigenome editing.