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

Jorge Alonso-Pérez¹  Jordi Díaz-Manera¹  Miguel Ángel Rubio²  Andrés Nascimento³  Carlos Ortez³  Verónica Saez³  Daniel Natera-de Benito³  Alicia Martínez-Piñeiro⁴  Gisela Nogales-Gadea⁴  Mònica Suelves⁴  Emma Koehorst⁴  Renato Odria⁴  Judit Núñez-Manchón⁴  Júlia Capó⁴  Ian Linares-Pardo⁴  Giuseppe Lucente⁴  Agustín Rodriguez-Palmero⁴  Alba Ramos-Fransi⁴  Andrea Arbex⁴  Miriam Almendrote⁴ 

[1] Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain;Neuromuscular Unit, Department of Neurology, Hospital del Mar, 08003 Barcelona, Spain;Neuromuscular Unit, Neuropediatric Department, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, L’Hospitalet de Llobregat, 08950 Barcelona, Spain;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;

关键词: myotonic dystrophy;    CpG islands;    DNA methylation;    epigenetics;    phenotype severity;    DM1 biopsies;   

DOI  :  10.3390/biomedicines10061372

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown