BACKGROUND: Pulmonary fibrosis is a relentless and ultimately fatal lung disorder. Despite a wealth of research, the intricate molecular pathways that contribute to the onset of PF, especially the aspects related to epigenetic modifications and chromatin dynamics, continue to be elusive and not fully understood. METHODS: Utilizing a bleomycin-induced pulmonary fibrosis model, we conducted a comprehensive analysis of the interplay between chromatin structure, chromatin accessibility, gene expression patterns, and cellular heterogeneity. Our chromatin structure analysis included 5 samples (2 control and 3 bleomycin-treated), while accessibility and expression analysis included 6 samples each (3 control and 3 bleomycin-treated). RESULTS: We found that chromatin architecture, with its alterations in compartmentalization and accessibility, is positively correlated with genome-wide gene expression changes during fibrosis. The importance of immune system inflammation and extracellular matrix reorganization in fibrosis is underscored by these chromatin alterations. Transcription factors such as PU.1, AP-1, and IRF proteins, which are pivotal in immune regulation, are associated with an increased abundance of their motifs in accessible genomic regions and are correlated with highly expressed genes. CONCLUSIONS: We identified 14 genes that demonstrated consistent changes in their expression, accessibility, and compartmentalization, suggesting their potential as promising targets for the development of treatments for lung fibrosis.