Integrative analyses of gene expression profile reveal potential crucial roles of mitotic cell cycle and microtubule cytoskeleton in pulmonary artery hypertension

Luo, Jing; Li, Haiyan; Liu, Zhenwei; Li, Chenlu; Wang, Ruochen; Fang, Jinxia; Lu, Saisai; Guo, Jing; Zhu, Xiongzhao; Wang, Xiaobing

doi:10.1186/s12920-020-00740-x

Cited by 18 publications

(18 citation statements)

References 61 publications

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“…Downregulated expression of SMC1A, SMC3, and SMC4 could induce growth suppression in lung cancer cells via G1/S cell cycle phase arrest and the apoptosis pathway (Zhang et al, 2013). Another PAH integrative analysis revealed that SMC2 and SMC4 were high hubs and verified their increased expression in PAH patients compared to control patients (Luo et al, 2020). The SMCs family plays key roles in the mitotic cell division machinery (Dávalos et al, 2012), indicating that SMCs might be regulators of cell proliferation.…”

Section: Discussionmentioning

confidence: 91%

“…Then, a machine learning-based microarray analysis showed that low-expression genes could also be extremely informative at predicting and distinguishing among different forms of PAH (Cui et al, 2019). Recently, a transcriptomic analysis of PASMCs revealed that genes related to cell proliferation and mitosis are increased in PAH (Luo et al, 2020). However, to date, most studies have been focused on PAHs associated with single disease (Desai et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Comparative Transcriptional Analysis of Pulmonary Arterial Hypertension Associated With Three Different Diseases

Wang

Jiang

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Pulmonary arterial hypertension (PAH) is a severe cardiovascular disorder with high mortality. Multiple clinical diseases can induce PAH, but the underlying molecular mechanisms shared in PAHs associated with different diseases remain unclear. The aim of this study is to explore the key candidate genes and pathways in PAH associated with congenital heart disease (CHD-PAH), PAH associated with connective tissue disease (CTD-PAH), and idiopathic PAH (IPAH). We performed differential expression analysis based on a public microarray dataset GSE113439 and identified 1,442 differentially expressed genes, of which 80.3% were upregulated. Subsequently, both pathway enrichment analysis and protein–protein interaction network analysis revealed that the “Cell cycle” and “DNA damage” processes were significantly enriched in PAH. The expression of seven upregulated candidate genes (EIF2AK2, TOPBP1, CDC5L, DHX15, and CUL1–3) and three downregulated candidate genes (DLL4, EGFL7, and ACE) were validated by qRT-PCR. Furthermore, cell cycle-related genes Cul1 and Cul2 were identified in pulmonary arterial endothelial cells (PAECs) in vitro. The result revealed an increased expression of Cul2 in PAECs after hypoxic treatment. Silencing Cul2 could inhibit overproliferation and migration of PAECs in hypoxia. Taken together, according to bioinformatic analyses, our work revealed that “Cell cycle” and “DNA damage” process-related genes and pathways were significantly dysregulated expressed in PAHs associated with three different diseases. This commonality in molecular discovery might broaden the genetic perspective and understanding of PAH. Besides, silencing Cul2 showed a protective effect in PAECs in hypoxia. The results may provide new treatment targets in multiple diseases induced by PAH.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Comparative Transcriptional Analysis of Pulmonary Arterial Hypertension Associated With Three Different Diseases

Wang

Jiang

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…Although the previous study yielded some promising biomarkers, we are still skeptical about whether changes in PBMCs at the transcriptomic level can genuinely signal the development of PAH in the lungs. Moreover, some studies have already examined the data sets in this study; however, compared to their conclusion based on differential expression analysis, WGCNA focuses on the interaction between genes in the systemic level and minimizes the loss of information by using soft thresholding (11)(12)(13).…”

Section: Discussionmentioning

confidence: 99%

“…It has been successfully applied in some fields, such as breast cancer (9,10). Similarly, the high-throughput strategies also have been applied in the field of PAH (11,12). However, the selection gene features based on differential expression between 2 groups neglects the potential relationships between each gene.…”

Section: Introductionmentioning

confidence: 99%

ECM2 and GLT8D2 in human pulmonary artery hypertension: fruits from weighted gene co-expression network analysis

Bai¹,

Xu²,

Dai³

et al. 2021

J Thorac Dis

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Background:Pulmonary artery hypertension (PAH) is an incurable disease with a high mortality rate.Current medications ameliorate symptoms but cannot target adverse vascular remodeling. New therapeutic strategies for PAH need to be established. Methods:Using the weighted gene coexpression network analysis (WGCNA) algorithm, we constructed a coexpression network of dataset GSE117261 from the Gene Expression Omnibus (GEO) database. Key modules were identified by the relationship between module eigengenes and clinical traits. Hub genes were screened out based on gene significance (GS), module membership (MM), and mean pulmonary artery pressure (mPAP). External validations were conducted in GSE48149 and GSE113439. Functional enrichment and immune cell infiltration were analyzed using Metascape and CIBERSORTx. Results:The WGCNA analysis revealed 13 coexpression modules. The pink module had the highest correlation with PAH in terms of module eigengene (r=0.79; P=2e−18) and module significance (MS =0.43).Functional enrichment indicated genes in the pink module contributed to the immune system process and extracellular matrix (ECM). In the pink module, ECM2 (GS =0.65, MM =0.86, ρ=0.407, P=0.0019) and GLT8D2 (GS =0.63, MM =0.85, ρ=0.443, P=0.006) were identified as hub genes. For immune cells infiltration in PAH lung tissue, hub genes were positively correlated with M2 macrophages and resting mast cells, and were negatively correlated with monocytes, neutrophils, and CD4-naïve T cells. Conclusions:Our research identified 2 hub genes ECM2 and GLT8D2 related to PAH. The functions of these hub genes were involved in the immune process and ECM, indicating that they might serve as candidate therapeutic targets for PAH.

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“…A core subunit of condensin complexes Enriched in facilitating mitotic cell cycle process in PAH (Luo et al, 2020).…”

Section: Smc4mentioning

confidence: 99%

Molecular Characterization and Elucidation of Pathways to Identify Novel Therapeutic Targets in Pulmonary Arterial Hypertension

et al. 2021

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Background: Pulmonary arterial hypertension (PAH) is a life-threatening chronic cardiopulmonary disease. However, there are limited studies reflecting the available biomarkers from separate gene expression profiles in PAH. This study explored two microarray datasets by an integrative analysis to estimate the molecular signatures in PAH.Methods: Two microarray datasets (GSE53408 and GSE113439) were exploited to compare lung tissue transcriptomes of patients and controls with PAH and to estimate differentially expressed genes (DEGs). According to common DEGs of datasets, gene and protein overrepresentation analyses, protein–protein interactions (PPIs), DEG–transcription factor (TF) interactions, DEG–microRNA (miRNA) interactions, drug–target protein interactions, and protein subcellular localizations were conducted in this study.Results: We obtained 38 common DEGs for these two datasets. Integration of the genome transcriptome datasets with biomolecular interactions revealed hub genes (HSP90AA1, ANGPT2, HSPD1, HSPH1, TTN, SPP1, SMC4, EEA1, and DKC1), TFs (FOXC1, FOXL1, GATA2, YY1, and SRF), and miRNAs (hsa-mir-17-5p, hsa-mir-26b-5p, hsa-mir-122-5p, hsa-mir-20a-5p, and hsa-mir-106b-5p). Protein–drug interactions indicated that two compounds, namely, nedocromil and SNX-5422, affect the identification of PAH candidate biomolecules. Moreover, the molecular signatures were mostly localized in the extracellular and nuclear areas.Conclusions: In conclusion, several lung tissue-derived molecular signatures, highlighted in this study, might serve as novel evidence for elucidating the essential mechanisms of PAH. The potential drugs associated with these molecules could thus contribute to the development of diagnostic and therapeutic strategies to ameliorate PAH.

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Integrative analyses of gene expression profile reveal potential crucial roles of mitotic cell cycle and microtubule cytoskeleton in pulmonary artery hypertension

Cited by 18 publications

References 61 publications

Comparative Transcriptional Analysis of Pulmonary Arterial Hypertension Associated With Three Different Diseases

Comparative Transcriptional Analysis of Pulmonary Arterial Hypertension Associated With Three Different Diseases

ECM2 and GLT8D2 in human pulmonary artery hypertension: fruits from weighted gene co-expression network analysis

Molecular Characterization and Elucidation of Pathways to Identify Novel Therapeutic Targets in Pulmonary Arterial Hypertension

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