Expanded CAG/CTG repeats resist gene silencing mediated by targeted epigenome editing.

Details

Serval ID
serval:BIB_7591BC227110
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Expanded CAG/CTG repeats resist gene silencing mediated by targeted epigenome editing.
Journal
Human molecular genetics
Author(s)
Yang B., Borgeaud A.C., Buřičová M., Aeschbach L., Rodríguez-Lima O., Ruiz Buendía G.A., Cinesi C., Taylor A.S., Baubec T., Dion V.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Publication state
Published
Issued date
03/02/2022
Peer-reviewed
Oui
Volume
31
Number
3
Pages
386-398
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
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. Previous studies have implicated the histone deacetylase HDAC5 and the DNA methyltransferase DNMT1 as modulators of repeat instability via mechanisms that are not fully understood. Using PInT, we found no evidence that HDAC5 or 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 targeting HDAC5 and DNMT1. 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.
Pubmed
Web of science
Open Access
Yes
Create date
04/10/2021 13:18
Last modification date
20/07/2022 6:38
Usage data