Genomic Reorganization of Lamin-Associated Domains in Cardiac Myocytes Is Associated With Differential Gene Expression and DNA Methylation in Human Dilated Cardiomyopathy
Genomic Reorganization of Lamin-Associated Domains in Cardiac Myocytes Is Associated With Differential Gene Expression and DNA Methylation in Human Dilated Cardiomyopathy
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DOI：
10.1161/circresaha.118.314177
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发表时间：
2019-04-12
影响因子：
20.1
通讯作者：
Marian, Ali J.
中科院分区：
文献类型：
--
作者：
Cheedipudi, Sirisha M.;Matkovich, Scot J.;Marian, Ali J.
理由：核膜蛋白LMNA（lamin a/c）通过层粘连蛋白相关结构域（LAD）与基因组相互作用，并调节基因表达。 LMNA基因中的突变引起各种各样的疾病，包括扩张的心肌病（DCM）。 DCM是椎板病中死亡的主要原因。原则：识别leads并表征其与DCM的人体心肌细胞中CpG甲基化和基因表达的相关性，并结果：LMNA染色质免疫沉淀 - 再生，减少了代表性的Bisulfite bisulfite序列和RNA-序列和RNA-序列和RNA-序列和RNA-序列，并在5对照和5 LMNA相关的DCM中进行测序心。使用富集的域检测器程序确定了LAD。全基因组331 +/- 77个小伙子在对照人心肌细胞中鉴定出平均2.1 +/- 1.5 Mbp。 LAD涵盖了大约20％的基因组，主要位于异染色质中，而在启动子和积极转录的区域中则较少。在DCM中重新分布了LAD，这可以证明520的增益和149个基因组区域的损失。在DCM中，大约有4500个编码基因和800个长的非编码RNA，其水平与顺式中的编码基因的转录水平相关。 TP53（肿瘤蛋白53）是失调途径中最突出的。在对照和DCM心脏中，CpG位点主要是全甲基化的基因组，但DCM中总体CpG甲基化增加了。 LAD与CpG甲基化增加和抑制基因表达有关。综合分析确定了其表达的基因，其表达受到LAD或CPG甲基化的调节，或者两者都与涉及细胞死亡，细胞周期和代谢调节的基因有关的后者。结论：LADS涵盖人类心脏肌细胞中大约20％的基因组的LADS包括数百个编码和非编码基因。与LMNA相关的DCM重新分布，与CpG甲基化和基因表达明显改变。因此，通过基因组改变的小伙子有助于椎板病中DCM的发病机理。
Rationale: LMNA (Lamin A/C), a nuclear membrane protein, interacts with genome through lamin-associated domains (LADs) and regulates gene expression. Mutations in the LMNA gene cause a diverse array of diseases, including dilated cardiomyopathy (DCM). DCM is the leading cause of death in laminopathies.Objective: To identify LADs and characterize their associations with CpG methylation and gene expression in human cardiac myocytes in DCM.Methods and Results: LMNA chromatin immunoprecipitation-sequencing, reduced representative bisulfite sequencing, and RNA-sequencing were performed in 5 control and 5 LMNA-associated DCM hearts. LADs were identified using enriched domain detector program. Genome-wide 331 +/- 77 LADs with an average size of 2.1 +/- 1.5 Mbp were identified in control human cardiac myocytes. LADs encompassed approximate to 20% of the genome and were predominantly located in the heterochromatin and less so in the promoter and actively transcribed regions. LADs were redistributed in DCM as evidenced by a gain of 520 and loss of 149 genomic regions. Approximately, 4500 coding genes and 800 long noncoding RNAs, whose levels correlated with the transcript levels of coding genes in cis, were differentially expressed in DCM. TP53 (tumor protein 53) was the most prominent among the dysregulated pathways. CpG sites were predominantly hypomethylated genome-wide in controls and DCM hearts, but overall CpG methylation was increased in DCM. LADs were associated with increased CpG methylation and suppressed gene expression. Integrated analysis identified genes whose expressions were regulated by LADs or CpG methylation, or by both, the latter pertained to genes involved in cell death, cell cycle, and metabolic regulation.Conclusions: LADs encompass approximate to 20% of the genome in human cardiac myocytes comprised several hundred coding and noncoding genes. LADs are redistributed in LMNA-associated DCM in association with markedly altered CpG methylation and gene expression. Thus, LADs through genomic alterations contribute to the pathogenesis of DCM in laminopathies.