Trans-generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy.
ATAC sequencing
DMD Exon skipping
iPSC Reprogramming
lncRNAs
trans-generational epigenetic inheritance
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 08 2020
07 08 2020
Historique:
received:
22
01
2020
revised:
05
06
2020
accepted:
08
06
2020
pubmed:
1
7
2020
medline:
19
8
2021
entrez:
30
6
2020
Statut:
ppublish
Résumé
Exon skipping is an effective strategy for the treatment of many Duchenne Muscular Dystrophy (DMD) mutations. Natural exon skipping observed in several DMD cases can help in identifying novel therapeutic tools. Here, we show a DMD study case where the lack of a splicing factor (Celf2a), which results in exon skipping and dystrophin rescue, is due to a maternally inherited trans-generational epigenetic silencing. We found that the study case and his mother express a repressive long non-coding RNA, DUXAP8, whose presence correlates with silencing of the Celf2a coding region. We also demonstrate that DUXAP8 expression is lost upon cell reprogramming and that, upon induction of iPSCs into myoblasts, Celf2a expression is recovered leading to the loss of exon skipping and loss of dystrophin synthesis. Finally, CRISPR/Cas9 inactivation of the splicing factor Celf2a was proven to ameliorate the pathological state in other DMD backgrounds establishing Celf2a ablation or inactivation as a novel therapeutic approach for the treatment of Duchenne Muscular Dystrophy.
Identifiants
pubmed: 32596946
doi: 10.15252/emmm.202012063
pmc: PMC7411655
doi:
Substances chimiques
Dystrophin
0
Oligonucleotides, Antisense
0
Banques de données
GEO
['GSE139571']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12063Subventions
Organisme : ERC-2019-SyG
ID : 855923-ASTRA
Pays : International
Organisme : Fondazione Telethon (Telethon Foundation)
ID : GGP16213
Pays : International
Organisme : Parent Project Italia
Pays : International
Organisme : Associazione Italiana per la Ricerca sul Cancro (AIRC)
ID : IG 2019 Id. 23053
Pays : International
Organisme : PRIN 2017
ID : 2017P352Z4
Pays : International
Organisme : MEIC
ID : BFU2016-75008-P
Pays : International
Organisme : Sapienza Research Call
ID : RM118164363B1D21
Pays : International
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Methods Mol Biol. 2017;1468:1-9
pubmed: 27662865
Cell Rep. 2013 Mar 28;3(3):661-70
pubmed: 23478022
Stem Cell Res. 2016 Jul;17(1):140-7
pubmed: 27318155
Mol Ther. 2010 Sep;18(9):1675-82
pubmed: 20551908
Mol Ther. 2012 Nov;20(11):2134-42
pubmed: 22968481
Stem Cells. 2010 Oct;28(10):1728-40
pubmed: 20715179
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Genome Res. 2002 Jun;12(6):996-1006
pubmed: 12045153
Nucleic Acids Res. 2018 Jan 4;46(D1):D754-D761
pubmed: 29155950
Mol Cell. 2016 Nov 17;64(4):645-658
pubmed: 27863225
Mol Cell Biol. 2001 Feb;21(4):1285-96
pubmed: 11158314
Nucleic Acids Res. 2016 Jan 4;44(D1):D733-45
pubmed: 26553804
J Vis Exp. 2012 Oct 31;(68):
pubmed: 23149977
Nat Biotechnol. 2013 Jan;31(1):46-53
pubmed: 23222703
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Hum Mutat. 2015 Apr;36(4):395-402
pubmed: 25604253
Expert Opin Biol Ther. 2017 Feb;17(2):225-236
pubmed: 27936976
Oncotarget. 2016 Aug 5;8(32):52211-52224
pubmed: 28881724
Trends Genet. 2016 Dec;32(12):815-827
pubmed: 27836208
Dis Model Mech. 2015 Jul 1;8(7):755-66
pubmed: 26035390
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Cell Stem Cell. 2007 Jun 7;1(1):55-70
pubmed: 18371336
Genomics. 1988 Jan;2(1):90-5
pubmed: 3384440
Nat Commun. 2016 Jan 22;7:10488
pubmed: 26796035
Biotechniques. 2017 Feb 1;62(2):53-61
pubmed: 28193148
Nucleic Acids Res. 2013 Jan;41(Database issue):D991-5
pubmed: 23193258
Cell Stem Cell. 2017 Dec 7;21(6):819-833.e6
pubmed: 29220666
Curr Protoc Mol Biol. 2015 Jan 05;109:21.29.1-21.29.9
pubmed: 25559105
Nat Rev Neurol. 2019 Jul;15(7):373-386
pubmed: 31147635
Mol Ther. 2009 Aug;17(8):1418-26
pubmed: 19293776
Proc Natl Acad Sci U S A. 1990 Oct;87(20):7988-92
pubmed: 2172969
Nature. 2011 Mar 3;471(7336):68-73
pubmed: 21289626
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Mol Cell Biol. 2013 Feb;33(4):773-84
pubmed: 23230269
EMBO Mol Med. 2020 Aug 7;12(8):e12063
pubmed: 32596946
Cell Rep. 2014 Nov 6;9(3):1163-70
pubmed: 25437568
Mol Aspects Med. 2013 Jul-Aug;34(4):841-8
pubmed: 22982217