Integrated analysis of a gene correlation network identifies critical regulation of fibrosis by lncRNAs and TFs in idiopathic pulmonary fibrosis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WANG Fan ¹ , LI Pei ² , XU Fang ³ ,  LI Fengsen ¹

1. Hospital of Traditional Chinese Medicine Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830000, P. R. China;
2. Kelamayi City Dushanzi People’s Hospital, Kelamayi, Xinjiang 833699, P. R. China;
3. Xinjiang Medical University, Urumqi, Xinjiang 830000, P. R. China;

Corresponding author：

LI Fengsen, Email: fengsen602@163.com

Keywords：

Idiopathic pulmonary fibrosis; Long non-coding RNAs; Transcription factors; Gene expression

DOI：

10.7507/1671-6205.201909064

Video：

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Objective To investigate the key long non-coding RNAs (lncRNAs) and transcription factors (TFs) in idiopathic pulmonary fibrosis (IPF) by Bioinformatics analysis.Methods Bioinformatics analysis of three gene expression profiles from the Gene Expression Omnibus dataset (GSE2052, GSE44723, and GSE24206), including 42 IPF and 21 normal lung tissues, was performed in this study. Subsequently, differentially expressed genes (DEGs) were filtered, and key genes involved in signaling pathways and the DEG-associated protein-protein interaction network (PPI) were further analyzed. The filtered genes expression was determined by real-time quantitative polymerase chain reaction analysis.Results A total of 8483 aberrantly expressed genes were screened, and 29 overlapping genes were identified among these three datasets. A significant enrichment analysis of DEG-associated functions and pathways was further performed. A total of 18 modules were obtained from the DEG PPI network, and most of the modules were involved in polyubiquitination, Golgi vesicle transport, endocytosis and so on. The key genes were obtained through hypergeometric testing, and most of the corresponding genes were closely associated with ubiquitin-mediated proteolysis, the spliceosome, and the cell cycle. These differential expressed genes, such as lncMALAT1, E2F1 and YBX1, were detected in the peripheral blood of IPF patients when compared with those normal control subjects.Conclusion lncMALAT1, E2F1 and YBX1 might be possible regulators for the pathogenesis of idiopathic pulmonary fibrosis.

Citation： WANG Fan, LI Pei, XU Fang, LI Fengsen. Integrated analysis of a gene correlation network identifies critical regulation of fibrosis by lncRNAs and TFs in idiopathic pulmonary fibrosis. Chinese Journal of Respiratory and Critical Care Medicine, 2020, 19(6): 554-562. doi: 10.7507/1671-6205.201909064 Copy

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9.	Grammatikakis I, Panda AC, Abdelmohsen K, et al. Long noncoding RNAs (lncRNAs) and the molecular hallmarks of aging. Aging (Albany NY), 2014, 6(12): 992-1009.
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16.	Wang XM, Zhang Y, Kim HP, et al. Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med, 2006, 203(13): 2895-2906.
17.	Peng R, Sridhar S, Tyagi G, et al. Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease. PLoS ONE, 2013, 8(4): e59348.
18.	Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res, 2015, 43(7): e47.
19.	Eisen MB, Spellman PT, Brown PO, et al. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci, 1998, 95(25): 14863-14868.
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23.	Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res, 2015, 43: D447-D452.
24.	Smoot ME, Ono K, Ruscheinski J, et al. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics, 2011, 27(3): 431-432.
25.	Bandettini WP, Kellman P, Mancini C, et al. MultiContrast Delayed Enhancement (MCODE) improves detection of subendocardial myocardial infarction by late gadolinium enhancement cardiovascular magnetic resonance: a clinical validation study. J Cardiovasc Magn Reson, 2012, 14: 83.
26.	Bindea G, Mlecnik B, Hackl H, et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics, 2009, 25(8): 1091-1093.
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28.	中华医学会呼吸病学分会间质性肺疾病学组. 特发性肺纤维化诊断和治疗中国专家共识. 中华结核和呼吸杂志, 2016, 39(6): 427-432.
29.	Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements. Nature, 2011, 470(7333): 284-288.
30.	Kretz M, Siprashvili Z, Chu C, et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature, 2013, 493(7431): 231-235.
31.	Natoli G, Andrau JC. Noncoding transcription at enhancers: general principles and functional models. Annu Rev Genet, 2012, 46: 1-19.
32.	Zong X, Tripathi V, Prasanth KV. RNA splicing control: yet another gene regulatory role for long nuclear noncoding RNAs. RNA Biol, 2011, 8(6): 968-977.
33.	Sgalla G, Iovene B, Calvello M, et al. Idiopathic pulmonary fibrosis: pathogenesis and management. Respir Res, 2018, 19(1): 32.
34.	Li Y, Jiang D, Liang J, et al. Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. J Exp Med, 2011, 208(7): 1459-1471.
35.	Hecker L, Jagirdar R, Jin T, et al. Reversible differentiation of myofibroblasts by MyoD. Exp Cell Res, 2011, 317(13): 1914-1921.
36.	White ES, Thannickal VJ, Carskadon SL, et al. Integrin alpha4beta1 regulates migration across basement membranes by lung fibroblasts: a role for phosphatase and tensin homologue deleted on chromosome 10. Am J Respir Crit Care Med, 2003, 168(4): 436-442.
37.	Li Y, Bao C, Gu S, et al. Associations between novel genetic variants in the promoter region of and risk of colorectal cancer. Oncotarget, 2017, 8(54): 92604-92614.
38.	Li Z, Ma Z, Xu X. Long non-coding RNA MALAT1 correlates with cell viability and mobility by targeting miR-22-3p in renal cell carcinoma via the PI3K/Akt pathway. Oncol Rep, 2019, 41(2): 1113-1121.
39.	Lin LP, Niu GH, Zhang XQ. Influence of lncRNA MALAT1 on septic lung injury in mice through p38 MAPK/p65 NF-κB pathway. Eur Rev Med Pharmacol Sci, 2019, 23(3): 1296-1304.
40.	Chen J, Wang S, Yu W, et al. MALAT1/miR-144/Brg1: a potential regulated axis of inflammation in myocardial ischemia-reperfusion injury. Int J Cardiol, 2019, 283: 151.
41.	Tian H, Wu M, Zhou P, et al. The long non-coding RNA MALAT1 is increased in renal ischemia-reperfusion injury and inhibits hypoxia-induced inflammation. Ren Fail, 2018, 40(1): 527-533.
42.	Huang S, Zhang L, Song J, et al. Long noncoding RNA MALAT1 mediates cardiac fibrosis in experimental postinfarct myocardium mice model. J Cell Physiol, 2019, 234(3): 2997-3006.
43.	Wu Y, Liu X, Zhou Q, et al. Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion. Toxicol Appl Pharmacol, 2015, 289(2): 163-176.
44.	Yan W, Wu Q, Yao W, et al. MiR-503 modulates epithelial-mesenchymal transition in silica-induced pulmonary fibrosis by targeting PI3K p85 and is sponged by lncRNA MALAT1. Sci Rep, 2017, 7(1): 11313.
45.	Sheu CC, Chang WA, Tsai MJ, et al. Gene expression changes associated with nintedanib treatment in idiopathic pulmonary fibrosis fibroblasts: a next-generation sequencing and bioinformatics study. J Clin Med, 2019, 8(3): E308.
46.	Suresh PS, Tsutsumi R, Venkatesh T. YBX1 at the crossroads of non-coding transcriptome, exosomal, and cytoplasmic granular signaling. Eur J Cell Biol, 2018, 97(3): 163-167.

1. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med, 2018, 378(19): 1811-1823.
2. Chambers RC, Mercer PF. Mechanisms of alveolar epithelial injury, repair, and fibrosis. Ann Am Thorac Soc, 2015, 12: S16-S20.
3. Hutchinson JP, McKeever TM, Fogarty AW, et al. Increasing global mortality from idiopathic pulmonary fibrosis in the twenty-first century. Ann Am Thorac Soc, 2014, 11: 1176-1185.
4. Raghu G, Rochwerg B, Zhang Y, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med, 2015, 192(2): e3-e19.
5. Selman M, King TE, Pardo A, et al. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med, 2001, 134(2): 136-151.
6. Harari S, Caminati A. IPF: new insight on pathogenesis and treatment. Allergy, 2010, 65(5): 537-553.
7. Leslie KO. Idiopathic pulmonary fibrosis may be a disease of recurrent, tractional injury to the periphery of the aging lung: a unifying hypothesis regarding etiology and pathogenesis. Arch Pathol Lab Med, 2012, 136(6): 591-600.
8. Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med, 2011, 208(7): 1339-1350.
9. Grammatikakis I, Panda AC, Abdelmohsen K, et al. Long noncoding RNAs (lncRNAs) and the molecular hallmarks of aging. Aging (Albany NY), 2014, 6(12): 992-1009.
10. Pandit KV, Milosevic J, Kaminski N. MicroRNAs in idiopathic pulmonary fibrosis. Transl Res, 2011, 157(4): 191-199.
11. Emblom-Callahan MC, Chhina MK, Shlobin OA, et al. Genomic phenotype of non-cultured pulmonary fibroblasts in idiopathic pulmonary fibrosis. Genomics, 2010, 96(3): 134-145.
12. Kass DJ, Kaminski N. Evolving genomic approaches to idiopathic pulmonary fibrosis: moving beyond genes. Clin Transl Sci, 2011, 4(5): 372-379.
13. Meltzer EB, Barry WT, D'Amico TA, et al. Bayesian probit regression model for the diagnosis of pulmonary fibrosis: proof-of-principle. BMC Med Genomics, 2011, 4: 70.
14. Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets-update. Nucleic Acids Res, 2013, 41: D991-D995.
15. Pardo A, Gibson K, Cisneros J, et al. Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. PLoS Med, 2005, 2(9): e251.
16. Wang XM, Zhang Y, Kim HP, et al. Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med, 2006, 203(13): 2895-2906.
17. Peng R, Sridhar S, Tyagi G, et al. Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease. PLoS ONE, 2013, 8(4): e59348.
18. Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res, 2015, 43(7): e47.
19. Eisen MB, Spellman PT, Brown PO, et al. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci, 1998, 95(25): 14863-14868.
20. Huang da W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res, 2009, 37(1): 1-13.
21. Harris MA, Clark J, Ireland A, et al. The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res, 2004, 32: D258-261.
22. Kanehisa M, Sato Y, Kawashima M, et al. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res, 2016, 44(D1): D457-D462.
23. Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res, 2015, 43: D447-D452.
24. Smoot ME, Ono K, Ruscheinski J, et al. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics, 2011, 27(3): 431-432.
25. Bandettini WP, Kellman P, Mancini C, et al. MultiContrast Delayed Enhancement (MCODE) improves detection of subendocardial myocardial infarction by late gadolinium enhancement cardiovascular magnetic resonance: a clinical validation study. J Cardiovasc Magn Reson, 2012, 14: 83.
26. Bindea G, Mlecnik B, Hackl H, et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics, 2009, 25(8): 1091-1093.
27. Maere S, Heymans K, Kuiper M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics, 2005, 21(16): 3448-3449.
28. 中华医学会呼吸病学分会间质性肺疾病学组. 特发性肺纤维化诊断和治疗中国专家共识. 中华结核和呼吸杂志, 2016, 39(6): 427-432.
29. Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements. Nature, 2011, 470(7333): 284-288.
30. Kretz M, Siprashvili Z, Chu C, et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature, 2013, 493(7431): 231-235.
31. Natoli G, Andrau JC. Noncoding transcription at enhancers: general principles and functional models. Annu Rev Genet, 2012, 46: 1-19.
32. Zong X, Tripathi V, Prasanth KV. RNA splicing control: yet another gene regulatory role for long nuclear noncoding RNAs. RNA Biol, 2011, 8(6): 968-977.
33. Sgalla G, Iovene B, Calvello M, et al. Idiopathic pulmonary fibrosis: pathogenesis and management. Respir Res, 2018, 19(1): 32.
34. Li Y, Jiang D, Liang J, et al. Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. J Exp Med, 2011, 208(7): 1459-1471.
35. Hecker L, Jagirdar R, Jin T, et al. Reversible differentiation of myofibroblasts by MyoD. Exp Cell Res, 2011, 317(13): 1914-1921.
36. White ES, Thannickal VJ, Carskadon SL, et al. Integrin alpha4beta1 regulates migration across basement membranes by lung fibroblasts: a role for phosphatase and tensin homologue deleted on chromosome 10. Am J Respir Crit Care Med, 2003, 168(4): 436-442.
37. Li Y, Bao C, Gu S, et al. Associations between novel genetic variants in the promoter region of and risk of colorectal cancer. Oncotarget, 2017, 8(54): 92604-92614.
38. Li Z, Ma Z, Xu X. Long non-coding RNA MALAT1 correlates with cell viability and mobility by targeting miR-22-3p in renal cell carcinoma via the PI3K/Akt pathway. Oncol Rep, 2019, 41(2): 1113-1121.
39. Lin LP, Niu GH, Zhang XQ. Influence of lncRNA MALAT1 on septic lung injury in mice through p38 MAPK/p65 NF-κB pathway. Eur Rev Med Pharmacol Sci, 2019, 23(3): 1296-1304.
40. Chen J, Wang S, Yu W, et al. MALAT1/miR-144/Brg1: a potential regulated axis of inflammation in myocardial ischemia-reperfusion injury. Int J Cardiol, 2019, 283: 151.
41. Tian H, Wu M, Zhou P, et al. The long non-coding RNA MALAT1 is increased in renal ischemia-reperfusion injury and inhibits hypoxia-induced inflammation. Ren Fail, 2018, 40(1): 527-533.
42. Huang S, Zhang L, Song J, et al. Long noncoding RNA MALAT1 mediates cardiac fibrosis in experimental postinfarct myocardium mice model. J Cell Physiol, 2019, 234(3): 2997-3006.
43. Wu Y, Liu X, Zhou Q, et al. Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion. Toxicol Appl Pharmacol, 2015, 289(2): 163-176.
44. Yan W, Wu Q, Yao W, et al. MiR-503 modulates epithelial-mesenchymal transition in silica-induced pulmonary fibrosis by targeting PI3K p85 and is sponged by lncRNA MALAT1. Sci Rep, 2017, 7(1): 11313.
45. Sheu CC, Chang WA, Tsai MJ, et al. Gene expression changes associated with nintedanib treatment in idiopathic pulmonary fibrosis fibroblasts: a next-generation sequencing and bioinformatics study. J Clin Med, 2019, 8(3): E308.
46. Suresh PS, Tsutsumi R, Venkatesh T. YBX1 at the crossroads of non-coding transcriptome, exosomal, and cytoplasmic granular signaling. Eur J Cell Biol, 2018, 97(3): 163-167.

Chinese Journal of Respiratory and Critical Care Medicine

Integrated analysis of a gene correlation network identifies critical regulation of fibrosis by lncRNAs and TFs in idiopathic pulmonary fibrosis

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