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| Status |
Public on Jul 20, 2021 |
| Title |
DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by high throughput sequencing
|
| Summary |
Mutations in LMNA, encoding Lamin A/C, lead to a variety of diseases known as laminopathies that include dilated cardiomyopathy (DCM). The role of epigenetic mechanisms. such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of patient-specific LMNA mutations on DNA methylation is unknown. To explore the role of DNA methylation in the context of unique LMNA mutations, we performed reduced representation bisulfite sequencing (RRBS) on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations. Family-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 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 near redistributed LADs. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of disease-associated genes dysregulated in LMNA mutated cells was uncovered, potentially due to aberrant methylation changes. In conclusion, the use of in vitro culture models of patient-derived cells and differential methylation analysis enabled the identification of epimutation hotspots and dysregulated genes, consistent with a Lamin A/C mutation-specific epigenetic disease mechanism that arose in somatic and early-developmental cell stages.
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| Overall design |
RRBS on 5 control (4 unaffected siblings and 1 unrelated donor) and 5 patient lines of fibroblasts and their iPSC derivatives from two families with DCM due to distinct LMNA mutations.
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| Contributor(s) |
Morival JL, Widyastuti HP, Nguyen CH, Zaragoza MV, Downing TL |
| Citation(s) |
34246298 |
| |
| Submission date |
Jan 06, 2021 |
| Last update date |
Jul 22, 2021 |
| Contact name |
Timothy Lamont Downing |
| E-mail(s) |
tim.downing@uci.edu
|
| Phone |
(949) 824-8744
|
| Organization name |
University of California Irvine
|
| Department |
Biomedical Engineering
|
| Lab |
Downing Lab
|
| Street address |
4151 Engineering Hall
|
| City |
Irvine |
| State/province |
CA |
| ZIP/Postal code |
92697 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA690116 |
| SRA |
SRP300677 |
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