Construction and validation of a histone-related gene signature for the diagnosis of endometriosis
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Abstract
Objectives: Endometriosis is a common chronic disease in childbearing women and a major cause of infertility. Our study aimed to identify and validate a novel gene signature for diagnosing endometriosis based on histone-related genes (HRGs), and to investigate their biological functions in endometriosis.
Material and methods: RNA sequence data were downloaded from the Gene Expression Omnibus database, and HRGs were retrieved from the GeneCards database. We identified differentially expressed genes using the limma package, and constructed a diagnostic model using the rms package. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed for visualization, annotation, and integrated discovery. Subsequently, we validated the model using the recall and decision curve analysis (DCA). Additionally, we analyzed the immune microenvironment features using CIBERSORT.
Results: A total of 18 differentially expressed HRGs were identified in patients with endometriosis compared with controls. GO and KEGG enrichment was mainly in spindle organization, positive regulation of the cell cycle process, progesterone-mediated oocyte maturation, and cellular senescence and cell cycle. We obtained a signature of four HRGs (JUNB, FRY, LMNB1, and SPAG1). DCA revealed that the diagnostic model benefits patients with endometriosis, regardless of the incidence. CIBERSORT analysis showed that the number of plasma cells increased significantly in endometriosis samples from all four datasets.
Conclusions: Our findings provide novel insights into the function of HRGs in the development of endometriosis and identify a new signature of four HRGs that may serve as valuable diagnostic markers and therapeutic targets for this disease.
Keywords: endometriosishistone-related genesdifferentially expressed genediagnosisGEO
References
- Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020; 382(13): 1244–1256.
- Allaire C, Bedaiwy MA, Yong PJ. Diagnosis and management of endometriosis. CMAJ. 2023; 195(10): E363–E371.
- Zhuo Z, Wang C, Yu H. Plasma microRNAs can be a potential diagnostic biomarker for endometriosis. Ginekologia Polska. 2022; 93(6): 450–459.
- Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021; 397(10276): 839–852.
- Martire S, Banaszynski LA. The roles of histone variants in fine-tuning chromatin organization and function. Nat Rev Mol Cell Biol. 2020; 21(9): 522–541.
- Neganova ME, Klochkov SG, Aleksandrova YR, et al. Histone modifications in epigenetic regulation of cancer: Perspectives and achieved progress. Semin Cancer Biol. 2022; 83: 452–471.
- Sun Y, Zhang H, Qiu T, et al. Epigenetic regulation of mesenchymal stem cell aging through histone modifications. Genes Dis. 2023; 10(6): 2443–2456.
- Xu H, Wu M, Ma X, et al. Function and Mechanism of Novel Histone Posttranslational Modifications in Health and Disease. Biomed Res Int. 2021; 2021: 6635225.
- Bonner ER, Dawood A, Gordish-Dressman H, et al. Pan-cancer atlas of somatic core and linker histone mutations. NPJ Genom Med. 2023; 8(1): 23.
- Hever A, Roth RB, Hevezi P, et al. Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator. Proc Natl Acad Sci U S A. 2007; 104(30): 12451–12456.
- Crispi S, Piccolo MT, D'Avino A, et al. Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects. J Cell Physiol. 2013; 228(9): 1927–1934.
- Tamaresis JS, Irwin JC, Goldfien GA, et al. Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology. 2014; 155(12): 4986–4999.
- Yu G, Wang LG, Han Y, et al. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5): 284–287.
- Walter W, Sánchez-Cabo F, Ricote M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics. 2015; 31(17): 2912–2914.
- Zhang H, Meltzer P, Davis S. RCircos: an R package for Circos 2D track plots. BMC Bioinformatics. 2013; 14: 244.
- Yan X, Zhai Li, Fan W. C-index: A weighted network node centrality measure for collaboration competence. Journal of Informetrics. 2013; 7(1): 223–239.
- Paraskevopoulou MD, Georgakilas G, Kostoulas N, et al. DIANA-LncBase: experimentally verified and computationally predicted microRNA targets on long non-coding RNAs. Nucleic Acids Res. 2013; 41(Database issue): D239–D245.
- Li JH, Liu S, Zhou H, et al. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Research. 2013; 42(D1): D92–D97.
- Ma He, Sun X, Wang Y, et al. Integrated analysis identified novel miRNAs and mRNA in endometriosis. Ginekol Pol. 2022 [Epub ahead of print].
- Millán-Zambrano G, Burton A, Bannister AJ, et al. Histone post-translational modifications - cause and consequence of genome function. Nat Rev Genet. 2022; 23(9): 563–580.
- Marquardt RM, Tran DN, Lessey BA, et al. Epigenetic Dysregulation in Endometriosis: Implications for Pathophysiology and Therapeutics. Endocr Rev. 2023; 44(6): 1074–1095.
- Casalechi M, Stefano GDi, Fornelli G, et al. Impact of endometriosis on the ovarian follicles. Best Practice & Research Clinical Obstetrics & Gynaecology. 2024; 92: 102430.
- Da Broi MG, Malvezzi H, Paz CCP, et al. Follicular fluid from infertile women with mild endometriosis may compromise the meiotic spindles of bovine metaphase II oocytes. Hum Reprod. 2014; 29(2): 315–323.
- Cheng YH, Huang CW, Lien HT, et al. A Preliminary Investigation of the Roles of Endometrial Cells in Endometriosis Development via In Vitro and In Vivo Analyses. International Journal of Molecular Sciences. 2024; 25(7): 3873.
- Lamceva J, Uljanovs R, Strumfa I. The Main Theories on the Pathogenesis of Endometriosis. Int J Mol Sci. 2023; 24(5).
- Lin X, Dai Y, Tong X, et al. Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility. Redox Biology. 2020; 30: 101431.
- Malvezzi H, Dobo C, Filippi RZ, et al. Altered p16, IL-1β, and Lamin b1 Protein Expression Suggest Cellular Senescence in Deep Endometriotic Lesions. Int J Mol Sci. 2022; 23(5).
- Zhang L, Liu H, Xiong W, et al. CircFOXO3 mediates hypoxia‐induced autophagy of endometrial stromal cells in endometriosis. The FASEB Journal. 2024; 38(5).
- Parra-Herran C, Bassiouny D, Lerner-Ellis J, et al. p53, Mismatch Repair Protein, and POLE Abnormalities in Ovarian Clear Cell Carcinoma. American Journal of Surgical Pathology. 2019; 43(12): 1591–1599.
- Fan D, Wang Xu, Shi Z, et al. Understanding endometriosis from an immunomicroenvironmental perspective. Chin Med J (Engl). 2023; 136(16): 1897–1909.
- Carbone G, Nelson K, Baumgartner C, et al. Endometriosis: Cell Death and Cell Signaling Machinery. Endocrinology. 2023; 164(6).
- Khoyratty TE, Ai Z, Ballesteros I, et al. Distinct transcription factor networks control neutrophil-driven inflammation. Nat Immunol. 2021; 22(9): 1093–1106.
- Ren Fj, Cai Xy, Yao Y, et al. JunB: a paradigm for Jun family in immune response and cancer. Frontiers in Cellular and Infection Microbiology. 2023; 13.
- Ahn SH, Edwards AK, Singh SS, et al. IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors. J Immunol. 2015; 195(6): 2591–2600.
- Liu Y, Chen X, Gong Z, et al. Fry Is Required for Mammary Gland Development During Pregnant Periods and Affects the Morphology and Growth of Breast Cancer Cells. Frontiers in Oncology. 2019; 9.
