Differential Gene Co-expression Network Analyses Reveal Novel Molecules Associated with Transcriptional Dysregulation of Key Biological Processes in Osteoarthritis Knee Cartilage

Overview

Journal Osteoarthr Cartil Open

Date 2022 Dec 7

PMID 36474801

Authors

I Buzzatto-Leite

J Afonso

B Silva-Vignato

L L Coutinho

L E Alvares

Affiliations

Soon will be listed here.

Abstract

Objectives: To compare co-expression networks of normal and osteoarthritis knee cartilage to uncover molecules associated with the transcriptional misregulation compromising biological processes (BPs) critical for cartilage homeostasis.

Design: Normal and osteoarthritis human knee cartilage RNA-seq GSE114007 dataset was obtained from the Gene Expression Omnibus database. Partial Correlation and Information Theory (PCIT) algorithm was used to build co-expression networks containing all nodes connecting to at least one differentially expressed gene (DEG) in normal and osteoarthritis networks. Hub and hub centrality genes were used to perform functional enrichment analysis. Enriched BPs known to be associated with both healthy and diseased cartilage were compared in depth.

Results: Differential co-expression network analyses allowed the identification of and as exclusively co-expressed with DEGs in normal and osteoarthritis networks, respectively. The top hub and hub centrality genes of these networks were and (normal) and (osteoarthritis). Enrichment analysis revealed several shared BPs between the contrasting groups, which are well-known in osteoarthritis pathogenesis. Protein-protein interaction network analysis for these BPs showed a global down-regulation of transcription factors in osteoarthritis. Specific transcription factors were identified as pleiotropic mediators in articular cartilage maintenance since they take part in several BPs. In addition, chromatin organisation and modification proteins were found relevant for osteoarthritis development.

Conclusion: Differential gene co-expression analysis allowed the identification of novel and high priority therapeutic candidate genes that may drive modifications in the transcriptional "status" of cartilage in osteoarthritis.

Citing Articles

Identification of diagnostic biomarkers for osteoarthritis through bioinformatics and machine learning.

Wang K, Li Y, Lin J Heliyon. 2024; 10(6):e27506.

PMID: 38496843 PMC: 10944228. DOI: 10.1016/j.heliyon.2024.e27506.

Pleiotropic Roles of a KEAP1-Associated Deubiquitinase, OTUD1.

Oikawa D, Shimizu K, Tokunaga F Antioxidants (Basel). 2023; 12(2).

PMID: 36829909 PMC: 9952104. DOI: 10.3390/antiox12020350.

References

Dudek M, Gossan N, Yang N, Im H, Ruckshanthi J, Yoshitane H . The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity. J Clin Invest. 2015; 126(1):365-76. PMC: 4701559. DOI: 10.1172/JCI82755. View

Yang B, Sun H, Jia M, He Y, Luo Y, Wang T . DNA damage-inducible transcript 3 restrains osteoclast differentiation and function. Bone. 2021; 153:116162. DOI: 10.1016/j.bone.2021.116162. View

Takeda Y, Jetten A . Prospero-related homeobox 1 (Prox1) functions as a novel modulator of retinoic acid-related orphan receptors α- and γ-mediated transactivation. Nucleic Acids Res. 2013; 41(14):6992-7008. PMC: 3737549. DOI: 10.1093/nar/gkt447. View

Goymer P . Network biology: why do we need hubs?. Nat Rev Genet. 2011; 9(9):650. DOI: 10.1038/nrg2450. View

Barabasi A, Oltvai Z . Network biology: understanding the cell's functional organization. Nat Rev Genet. 2004; 5(2):101-13. DOI: 10.1038/nrg1272. View

Park H, Kim J, Baek K . Regulation of Wnt Signaling through Ubiquitination and Deubiquitination in Cancers. Int J Mol Sci. 2020; 21(11). PMC: 7311976. DOI: 10.3390/ijms21113904. View

Wang F, Guo Z, Yuan Y . STAT3 speeds up progression of osteoarthritis through NF-κB signaling pathway. Exp Ther Med. 2019; 19(1):722-728. PMC: 6913305. DOI: 10.3892/etm.2019.8268. View

Sarkar M, Ghosh M . DEAD box RNA helicases: crucial regulators of gene expression and oncogenesis. Front Biosci (Landmark Ed). 2015; 21(2):225-50. DOI: 10.2741/4386. View

Haag J, Gebhard P, Aigner T . SOX gene expression in human osteoarthritic cartilage. Pathobiology. 2008; 75(3):195-9. DOI: 10.1159/000124980. View

10.

Hashimoto S, Nishiyama T, Hayashi S, Fujishiro T, Takebe K, Kanzaki N . Role of p53 in human chondrocyte apoptosis in response to shear strain. Arthritis Rheum. 2009; 60(8):2340-9. DOI: 10.1002/art.24706. View

11.

Lambert S, Jolma A, Campitelli L, Das P, Yin Y, Albu M . The Human Transcription Factors. Cell. 2018; 172(4):650-665. DOI: 10.1016/j.cell.2018.01.029. View

12.

Rim Y, Nam Y, Ju J . The Role of Chondrocyte Hypertrophy and Senescence in Osteoarthritis Initiation and Progression. Int J Mol Sci. 2020; 21(7). PMC: 7177949. DOI: 10.3390/ijms21072358. View

13.

Yang X, Chen H, Zheng H, Chen K, Cai P, Li L . LncRNA SNHG12 Promotes Osteoarthritis Progression Through Targeted Down-Regulation of miR-16-5p. Clin Lab. 2022; 68(1). DOI: 10.7754/Clin.Lab.2021.210402. View

14.

Hitchens M, Robbins P . The role of the transcription factor DP in apoptosis. Apoptosis. 2003; 8(5):461-8. DOI: 10.1023/a:1025586207239. View

15.

Herrera F, Yamaguchi T, Roelink H, Tjian R . Core promoter factor TAF9B regulates neuronal gene expression. Elife. 2014; 3:e02559. PMC: 4083437. DOI: 10.7554/eLife.02559. View

16.

Assenov Y, Ramirez F, Schelhorn S, Lengauer T, Albrecht M . Computing topological parameters of biological networks. Bioinformatics. 2007; 24(2):282-4. DOI: 10.1093/bioinformatics/btm554. View

17.

Bandara L, Buck V, Zamanian M, Johnston L, La Thangue N . Functional synergy between DP-1 and E2F-1 in the cell cycle-regulating transcription factor DRTF1/E2F. EMBO J. 1993; 12(11):4317-24. PMC: 413728. DOI: 10.1002/j.1460-2075.1993.tb06116.x. View

18.

McCarthy D, Chen Y, Smyth G . Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012; 40(10):4288-97. PMC: 3378882. DOI: 10.1093/nar/gks042. View

19.

Patke A, Young M, Axelrod S . Molecular mechanisms and physiological importance of circadian rhythms. Nat Rev Mol Cell Biol. 2019; 21(2):67-84. DOI: 10.1038/s41580-019-0179-2. View

20.

Ikeda R, Tsuchiya Y, Koike N, Umemura Y, Inokawa H, Ono R . REV-ERBα and REV-ERBβ function as key factors regulating Mammalian Circadian Output. Sci Rep. 2019; 9(1):10171. PMC: 6629614. DOI: 10.1038/s41598-019-46656-0. View