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DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies
Clinical Epigenetics ( IF 4.8 ) Pub Date : 2021-07-10 , DOI: 10.1186/s13148-021-01127-0
Julien L P Morival 1, 2, 3 , Halida P Widyastuti 4 , Cecilia H H Nguyen 4 , Michael V Zaragoza 4 , Timothy L Downing 1, 2, 3, 5
Affiliation  

Mutations 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. 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 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. Our 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.

中文翻译:


DNA 甲基化分析揭示扩张型心肌病相关核纤层蛋白病患者的表突变热点



编码核纤层蛋白 A/C 的 LMNA 突变会导致多种称为核纤层蛋白病的疾病,包括扩张型心肌病 (DCM) 和骨骼异常。尽管之前的研究已经调查了 DCM 患者细胞中基因表达的失调,但表观遗传(基因调控)机制(例如 DNA 甲基化)的作用尚未得到彻底研究。此外,家族特异性 LMNA 突变对 DNA 甲基化的影响尚不清楚。在这里,我们对十对成纤维细胞及其诱导多能干细胞 (iPSC) 衍生物进行了简化代表性重亚硫酸盐测序,这些纤维细胞来自两个由于不同的 LMNA 突变而患有 DCM 的家族,其中之一还诱导短指。通过比较患者和对照样本的 DNA 甲基化情况,鉴定了家族特异性差异甲基化区域 (DMR)。成纤维细胞 DMR 被发现富集远端调控特征和转录抑制染色质,并与受核纤层蛋白病影响的组织中发现的表型相关基因相关。这些 DMR 与全转录组表达数据和核纤层相关结构域 (LAD) 组织相结合,揭示了差异表达基因附近存在家族间表观突变热点,其中大多数位于 LMNA 相关 DCM 中重新分布的 LAD 之外。对成纤维细胞和 iPSC 中发现的 DMR 进行比较,确定了两种细胞类型中持续存在表观突变的区域。最后,异常甲基化的疾病相关基因网络揭示了参与骨骼和心脏发育的途径之间的潜在分子联系。 我们的结果确定了共享的和突变特异性的核纤层蛋白病表观突变景观,这些表观突变与在体细胞和早期发育细胞阶段出现的核纤层蛋白 A/C 突变介导的表观遗传异常一致。
更新日期:2021-07-12
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