Uncovering the Gene Regulatory Network of Endothelial Cells in Mouse Duchenne Muscular Dystrophy: Insights from Single-Nuclei RNA Sequencing Analysis.
Uncovering the Gene Regulatory Network of Endothelial Cells in Mouse Duchenne Muscular Dystrophy: Insights from Single-Nuclei RNA Sequencing Analysis.
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杜氏肌营养不良症是一种破坏性的疾病，由肌营养不良蛋白基因（DMD）突变引起，可导致心脏和呼吸衰竭。尽管内皮细胞（EC）在疾病进展中发挥着关键作用，但人们对DMD基因对EC基因调控网络的影响的了解有限。在我们的研究中，我们旨在通过利用单核RNA测序（snRNA-seq）来评估DMD突变小鼠和野生型对照小鼠骨骼肌EC的转录组学特征来填补这一知识空白。我们的研究结果表明，DMD突变导致多个长非编码RNA（LncRNA）的上调。此外，我们还发现，内皮细胞的代谢途径活性发生了改变，氧化磷酸化、糖酵解和丙酮酸代谢减少，嘌呤代谢和嘧啶代谢增加。总的来说，我们的研究为DMD中EC的基因调控程序提供了新的见解，并强调了在这一领域进一步研究的重要性。这项研究的结果对DMD患者的治疗策略的发展具有重要意义。简介：杜氏肌营养不良症（DMD）是一种严重的X连锁隐性疾病，由肌营养不良蛋白基因突变引起，可导致心脏和呼吸衰竭。尽管DMD对内皮细胞（EC）有重要影响，但对其对内皮基因网络的影响了解有限。本研究旨在探讨DMD对内皮细胞基因调控网络的影响。方法和结果：为了深入了解肌营养不良蛋白肌营养不良基因（DMD）在杜氏肌营养不良症EC中的作用;该研究利用单核RNA测序（snRNA-seq）来评估DMD突变小鼠（DMDmut）和野生型对照小鼠骨骼肌EC的转录组学特征。分析表明，DMD突变导致几个基因的抑制，包括SPTBN 1和多个长非编码RNA（lncRNA）的上调。GM 48099、GM 19951和GM 15564在来自DMDmut的EC和骨骼肌细胞中一致地上调，表明这些失调的lncRNA在不同细胞类型中是保守的。基因本体（GO）富集分析显示DMD突变激活了ECs中的以下四条途径：胞质胶原三聚体、带状胶原纤维、胶原三聚体复合物和嘌呤核苷酸代谢。研究还发现，EC的代谢途径活性发生了改变。氧化磷酸化（OXPHOS），脂肪酸降解，糖酵解，丙酮酸代谢减少，而嘌呤代谢，嘧啶代谢，叶酸和一个碳库增加。此外，该研究调查了DMD突变对骨骼肌EC的影响，发现其总数显着减少，但其增殖没有变化。结论：总的来说，这项研究为DMD中EC的基因调控程序提供了新的见解，并强调了在这一领域进一步研究的重要性。
Duchenne muscular dystrophy is a devastating disease that results from mutations in the dystrophin gene (DMD) and can lead to heart and respiratory failure. Despite the critical role of endothelial cells (ECs) in disease progression, there is limited understanding of the impact of the DMD gene on the gene regulatory network of ECs. In our study, we aimed to fill this knowledge gap by utilizing single-nuclei RNA sequencing (snRNA-seq) to evaluate the transcriptomic profile of ECs from skeletal muscle in DMD mutant mice and wild-type control mice. Our results showed that the DMD mutation resulted in the upregulation of multiple long noncoding RNAs (LncRNAs). Additionally, we found that the metabolic pathway activity of ECs was altered, with a decrease in oxidative phosphorylation, glycolysis, and pyruvate metabolism and an increase in purine metabolism and pyrimidine metabolism. Overall, our study provides new insights into the gene regulatory program in ECs in DMD and highlights the importance of further research in this area. The results of this study have important implications for the development of therapeutic strategies for patients with DMD. Introduction: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the dystrophin gene, which leads to heart and respiratory failure. Despite the critical impact of DMD on endothelial cells (ECs), there is limited understanding of its effect on the endothelial gene network. The aim of this study was to investigate the impact of DMD on the gene regulatory network of ECs. Methods and Results: To gain insights into the role of the dystrophin muscular dystrophy gene (DMD) in ECs from Duchenne muscular dystrophy; the study utilized single-nuclei RNA sequencing (snRNA-seq) to evaluate the transcriptomic profile of ECs from skeletal muscles in DMD mutant mice (DMDmut) and wild-type control mice. The analysis showed that the DMD mutation resulted in the suppression of several genes, including SPTBN1 and the upregulation of multiple long noncoding RNAs (lncRNAs). GM48099, GM19951, and GM15564 were consistently upregulated in ECs and skeletal muscle cells from DMDmut, indicating that these dysregulated lncRNAs are conserved across different cell types. Gene ontology (GO) enrichment analysis revealed that the DMD mutation activated the following four pathways in ECs: fibrillary collagen trimer, banded collagen fibril, complex of collagen trimers, and purine nucleotide metabolism. The study also found that the metabolic pathway activity of ECs was altered. Oxidative phosphorylation (OXPHOS), fatty acid degradation, glycolysis, and pyruvate metabolism were decreased while purine metabolism, pyrimidine metabolism, and one carbon pool by folate were increased. Moreover, the study investigated the impact of the DMD mutation on ECs from skeletal muscles and found a significant decrease in their overall number, but no change in their proliferation. Conclusions: Overall, this study provides new insights into the gene regulatory program in ECs in DMD and highlights the importance of further research in this area.
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影响因子：
3.7
作者：
Bovolenta M;Erriquez D;Valli E;Brioschi S;Scotton C;Neri M;Falzarano MS;Gherardi S;Fabris M;Rimessi P;Gualandi F;Perini G;Ferlini A
通讯作者：
Ferlini A
影响因子：
4.3
作者：
Filipp FV;Ratnikov B;De Ingeniis J;Smith JW;Osterman AL;Scott DA
通讯作者：
Scott DA
影响因子：
20.8
作者：
Facchinello N;Astone M;Audano M;Oberkersch RE;Spizzotin M;Calura E;Marques M;Crisan M;Mitro N;Santoro MM
通讯作者：
Santoro MM
短期暴露于高氧会导致培养的肺上皮细胞线粒体失调和小鼠肺泡简化。
影响因子：
3.6
作者：
Garcia D;Carr JF;Chan F;Peterson AL;Ellis KA;Scaffa A;Ghio AJ;Yao H;Dennery PA
通讯作者：
Dennery PA
DOI：
10.1152/ajpcell.00250.2016
发表时间：
2017-01-01
期刊：
American journal of physiology. Cell physiology
影响因子：
--
作者：
Lapel M;Weston P;Strassheim D;Karoor V;Burns N;Lyubchenko T;Paucek P;Stenmark KR;Gerasimovskaya EV
通讯作者：
Gerasimovskaya EV