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We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome\u2010wide association study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed DNA methylation data from whole\u2010blood samples in 179 patients with SSc and 241 unaffected individuals to identify differentially methylated positions (DMPs) with a false discovery rate (FDR) &lt;0.05. These results were further integrated with RNA sequencing data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This analysis yielded 525 DMPs enriched in immune\u2010related pathways, with leukocyte cell\u2013cell adhesion being the most significant (FDR = 4.91 \u00d7 10<jats:sup>\u22129<\/jats:sup>), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach, we observed an enrichment of neutrophil\u2010related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT\/enhancer\u2010binding protein transcription factor family in SSc, which is crucial in the myeloid lineage development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art43044-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.43044","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T01:28:37Z","timestamp":1730165317000},"page":"439-449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Strong Dysregulated Myeloid Component in the Epigenetic Landscape of Systemic Sclerosis: An Integrated DNA Methylome and Transcriptome Analysis"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0184-9543","authenticated-orcid":false,"given":"Javier","family":"Mart\u00ednez\u2010L\u00f3pez","sequence":"first","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez\u2010Neyra, Consejo Superior de Investigaciones Cient\u00edficas and Hospital Cl\u00ednico San Cecilio, Instituto de Investigaci\u00f3n Biosanitaria de Granada  Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0247-4280","authenticated-orcid":false,"given":"Lourdes","family":"Ortiz\u2010Fernandez","sequence":"additional","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez\u2010Neyra, Consejo Superior de Investigaciones Cient\u00edficas  Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elkyn","family":"Estupi\u00f1\u00e1n\u2010Moreno","sequence":"additional","affiliation":[{"name":"Josep Carreras Research Institute  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Kerick","sequence":"additional","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez\u2010Neyra, Consejo Superior de Investigaciones Cient\u00edficas  Granada 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