Omics Analyses of Stromal Cells from ACM Patients Reveal Alterations in Chromatin Organization and Mitochondrial Homeostasis.
Omics Analyses of Stromal Cells from ACM Patients Reveal Alterations in Chromatin Organization and Mitochondrial Homeostasis.
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DOI：
10.3390/ijms241210017
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发表时间：
2023-06-12
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
致心律失常性心肌病是一种以室性心律失常、心肌收缩功能障碍和心肌纤维脂肪替代为特征的遗传性疾病。心脏间充质基质细胞（CMSCs）通过向脂肪细胞和肌成纤维细胞分化参与疾病的发病机制。ACM中的一些改变的途径是已知的，但许多尚未被发现。我们的目的是通过比较ACM-CMSC与健康对照（HC）-CMSC的表观遗传和基因表达谱来丰富对ACM发病机制的理解。甲基化组分析确定了74个差异甲基化的核苷酸，其中大部分位于线粒体基因组。转录组分析揭示了327个基因在ACM与HC-CMSC中表达更多，202个基因表达更少。其中，涉及线粒体呼吸和上皮间充质转化的基因表达更多，细胞周期基因在ACM与HC-CMSC中表达较少。通过富集和基因网络分析，我们确定了差异调节途径，其中一些从未与ACM相关，包括线粒体功能和染色质组织，两者均与甲基化结果一致。功能验证证实，与对照组相比，ACM-CMSC表现出更高数量的活性线粒体和ROS产生，更低的增殖率和更明显的心外膜-间充质转化。总之，ACM-CMSC组学揭示了一些与疾病发病机制相关的额外改变的分子途径，这些分子途径可能构成特异性治疗的新靶点。
Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder characterized by ventricular arrhythmias, contractile dysfunctions and fibro-adipose replacement of myocardium. Cardiac mesenchymal stromal cells (CMSCs) participate in disease pathogenesis by differentiating towards adipocytes and myofibroblasts. Some altered pathways in ACM are known, but many are yet to be discovered. We aimed to enrich the understanding of ACM pathogenesis by comparing epigenetic and gene expression profiles of ACM-CMSCs with healthy control (HC)-CMSCs. Methylome analysis identified 74 differentially methylated nucleotides, most of them located on the mitochondrial genome. Transcriptome analysis revealed 327 genes that were more expressed and 202 genes that were less expressed in ACM- vs. HC-CMSCs. Among these, genes implicated in mitochondrial respiration and in epithelial-to-mesenchymal transition were more expressed, and cell cycle genes were less expressed in ACM- vs. HC-CMSCs. Through enrichment and gene network analyses, we identified differentially regulated pathways, some of which never associated with ACM, including mitochondrial functioning and chromatin organization, both in line with methylome results. Functional validations confirmed that ACM-CMSCs exhibited higher amounts of active mitochondria and ROS production, a lower proliferation rate and a more pronounced epicardial-to-mesenchymal transition compared to the controls. In conclusion, ACM-CMSC-omics revealed some additional altered molecular pathways, relevant in disease pathogenesis, which may constitute novel targets for specific therapies.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
--
作者：
Gerull B;Brodehl A
通讯作者：
Brodehl A
DOI：
10.1161/circgen.120.003273
发表时间：
2021-06
期刊：
Circulation. Genomic and precision medicine
影响因子：
--
作者：
James CA;Jongbloed JDH;Hershberger RE;Morales A;Judge DP;Syrris P;Pilichou K;Domingo AM;Murray B;Cadrin-Tourigny J;Lekanne Deprez R;Celeghin R;Protonotarios A;Asatryan B;Brown E;Jordan E;McGlaughon J;Thaxton C;Kurtz CL;van Tintelen JP
通讯作者：
van Tintelen JP
河马途径被激活，是心律失常性心肌病中脂肪形成的因果机制。
影响因子：
20.1
作者：
Chen SN;Gurha P;Lombardi R;Ruggiero A;Willerson JT;Marian AJ
通讯作者：
Marian AJ
影响因子：
5.8
作者：
Chiesa, Mattia;Colombo, Gualtiero I.;Piacentini, Luca
通讯作者：
Piacentini, Luca