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Article

An Integrative Analysis of DNA Methylation Pattern in Myotonic Dystrophy Type 1 Samples Reveals a Distinct DNA Methylation Profile between Tissues and a Novel Muscle-Associated Epigenetic Dysregulation

1
Neuromuscular and Neuropediatric Research Group, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Campus Can Ruti, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
2
Neuromuscular Pathology Unit, Neurology Service, Neuroscience Department, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain
3
Neuromuscular Unit, Neuropediatric Department, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, L’Hospitalet de Llobregat, 08950 Barcelona, Spain
4
Neuromuscular Unit, Department of Neurology, Hospital del Mar, 08003 Barcelona, Spain
5
Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
6
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK
7
Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Nina Entelis
Biomedicines 2022, 10(6), 1372; https://doi.org/10.3390/biomedicines10061372
Received: 22 April 2022 / Revised: 31 May 2022 / Accepted: 7 June 2022 / Published: 10 June 2022
(This article belongs to the Section Molecular Genetics and Genetic Diseases)
Myotonic dystrophy type 1 (DM1) is a progressive, non-treatable, multi-systemic disorder. To investigate the contribution of epigenetics to the complexity of DM1, we compared DNA methylation profiles of four annotated CpG islands (CpGis) in the DMPK locus and neighbouring genes, in distinct DM1 tissues and derived cells, representing six DM1 subtypes, by bisulphite sequencing. In blood, we found no differences in CpGi 74, 43 and 36 in DNA methylation profile. In contrast, a CTCF1 DNA methylation gradient was found with 100% methylation in congenital cases, 50% in childhood cases and 13% in juvenile cases. CTCF1 methylation correlated to disease severity and CTG expansion size. Notably, 50% of CTCF1 methylated cases showed methylation in the CTCF2 regions. Additionally, methylation was associated with maternal transmission. Interestingly, the evaluation of seven families showed that unmethylated mothers passed on an expansion of the CTG repeat, whereas the methylated mothers transmitted a contraction. The analysis of patient-derived cells showed that DNA methylation profiles were highly preserved, validating their use as faithful DM1 cellular models. Importantly, the comparison of DNA methylation levels of distinct DM1 tissues revealed a novel muscle-specific epigenetic signature with methylation of the CTCF1 region accompanied by demethylation of CpGi 43, a region containing an alternative DMPK promoter, which may decrease the canonical promoter activity. Altogether, our results showed a distinct DNA methylation profile across DM1 tissues and uncovered a novel and dual epigenetic signature in DM1 muscle samples, providing novel insights into the epigenetic changes associated with DM1. View Full-Text
Keywords: myotonic dystrophy; CpG islands; DNA methylation; epigenetics; phenotype severity; DM1 biopsies; cellular models myotonic dystrophy; CpG islands; DNA methylation; epigenetics; phenotype severity; DM1 biopsies; cellular models
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MDPI and ACS Style

Koehorst, E.; Odria, R.; Capó, J.; Núñez-Manchón, J.; Arbex, A.; Almendrote, M.; Linares-Pardo, I.; Natera-de Benito, D.; Saez, V.; Nascimento, A.; Ortez, C.; Rubio, M.Á.; Díaz-Manera, J.; Alonso-Pérez, J.; Lucente, G.; Rodriguez-Palmero, A.; Ramos-Fransi, A.; Martínez-Piñeiro, A.; Nogales-Gadea, G.; Suelves, M. An Integrative Analysis of DNA Methylation Pattern in Myotonic Dystrophy Type 1 Samples Reveals a Distinct DNA Methylation Profile between Tissues and a Novel Muscle-Associated Epigenetic Dysregulation. Biomedicines 2022, 10, 1372. https://doi.org/10.3390/biomedicines10061372

AMA Style

Koehorst E, Odria R, Capó J, Núñez-Manchón J, Arbex A, Almendrote M, Linares-Pardo I, Natera-de Benito D, Saez V, Nascimento A, Ortez C, Rubio MÁ, Díaz-Manera J, Alonso-Pérez J, Lucente G, Rodriguez-Palmero A, Ramos-Fransi A, Martínez-Piñeiro A, Nogales-Gadea G, Suelves M. An Integrative Analysis of DNA Methylation Pattern in Myotonic Dystrophy Type 1 Samples Reveals a Distinct DNA Methylation Profile between Tissues and a Novel Muscle-Associated Epigenetic Dysregulation. Biomedicines. 2022; 10(6):1372. https://doi.org/10.3390/biomedicines10061372

Chicago/Turabian Style

Koehorst, Emma, Renato Odria, Júlia Capó, Judit Núñez-Manchón, Andrea Arbex, Miriam Almendrote, Ian Linares-Pardo, Daniel Natera-de Benito, Verónica Saez, Andrés Nascimento, Carlos Ortez, Miguel Ángel Rubio, Jordi Díaz-Manera, Jorge Alonso-Pérez, Giuseppe Lucente, Agustín Rodriguez-Palmero, Alba Ramos-Fransi, Alicia Martínez-Piñeiro, Gisela Nogales-Gadea, and Mònica Suelves. 2022. "An Integrative Analysis of DNA Methylation Pattern in Myotonic Dystrophy Type 1 Samples Reveals a Distinct DNA Methylation Profile between Tissues and a Novel Muscle-Associated Epigenetic Dysregulation" Biomedicines 10, no. 6: 1372. https://doi.org/10.3390/biomedicines10061372

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