RT Journal Article
SR Electronic
T1 Expanded CAG/CTG Repeats Resist Gene Silencing Mediated by Targeted Epigenome Editing
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 368480
DO 10.1101/368480
A1 Bin Yang
A1 Alicia C. Borgeaud
A1 Lorène Aeschbach
A1 Oscar Rodríguez-Lima
A1 Gustavo A. Ruiz Buendía
A1 Cinzia Cinesi
A1 Tuncay Baubec
A1 Vincent Dion
YR 2020
UL http://biorxiv.org/content/early/2020/10/12/368480.abstract
AB Expanded CAG/CTG repeat disorders affect over 1 in 2500 individuals worldwide. Potential therapeutic avenues include gene silencing and modulation of repeat instability. However, there are major mechanistic gaps in our understanding of these processes, which prevent the rational design of an efficient treatment. To address this, we developed a novel system, ParB/ANCHOR-mediated Inducible Targeting (PInT), in which any protein can be recruited at will to a GFP reporter containing an expanded CAG/CTG repeat. Using PInT, we found no evidence that the histone deacetylase HDAC5 or the DNA methyltransferase DNMT1 modulate repeat instability upon targeting to the expanded repeat, suggesting that their effect is independent of local chromatin structure. Unexpectedly, we found that expanded CAG/CTG repeats reduce the effectiveness of gene silencing mediated by HDAC5 or DNMT1 targeting. The repeat-length effect in gene silencing by HDAC5 was abolished by a small molecule inhibitor of HDAC3. Our results have important implications on the design of epigenome editing approaches for expanded CAG/CTG repeat disorders. PInT is a versatile synthetic system to study the effect of any sequence of interest on epigenome editing.Competing Interest StatementThe authors have declared no competing interest.