DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies

Clinical Epigenetics

Julien L. P. Morival¹  Timothy L. Downing²  Michael V. Zaragoza³  Halida P. Widyastuti³  Cecilia H. H. Nguyen³ 

[1] Department of Biomedical Engineering and The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California Irvine, 2408 Engineering III, 92697, Irvine, CA, USA;NSF-Simons Center for Multiscale Cell Fate Research, University of California Irvine, Irvine, CA, USA;Center for Complex Biological Systems, University of California Irvine, Irvine, CA, USA;Department of Biomedical Engineering and The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California Irvine, 2408 Engineering III, 92697, Irvine, CA, USA;NSF-Simons Center for Multiscale Cell Fate Research, University of California Irvine, Irvine, CA, USA;Center for Complex Biological Systems, University of California Irvine, Irvine, CA, USA;Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA, USA;UCI Cardiogenomics Program, Department of Pediatrics, Division of Genetics and Genomics and Department of Biological Chemistry, University of California Irvine, 2042 Hewitt Hall, 92697, Irvine, CA, USA;

关键词: DNA methylation;    Lamin A/C;    Dilated cardiomyopathy;    Brachydactyly;   

DOI  :  10.1186/s13148-021-01127-0

来源: Springer

【 摘 要 】

BackgroundMutations in LMNA, encoding lamin A/C, lead to a variety of diseases known as laminopathies including dilated cardiomyopathy (DCM) and skeletal abnormalities. Though previous studies have investigated the dysregulation of gene expression in cells from patients with DCM, the role of epigenetic (gene regulatory) mechanisms, such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of family-specific LMNA mutations on DNA methylation is unknown. Here, we performed reduced representation bisulfite sequencing on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations, one of which also induces brachydactyly.ResultsFamily-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in tissues affected by laminopathies. These DMRs, in combination with transcriptome-wide expression data and lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located outside LADs redistributed in LMNA-related DCM. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of aberrantly methylated disease-associated genes revealed a potential molecular link between pathways involved in bone and heart development.ConclusionsOur results identified both shared and mutation-specific laminopathy epimutation landscapes that were consistent with lamin A/C mutation-mediated epigenetic aberrancies that arose in somatic and early developmental cell stages.

【 授权许可】

CC BY