Epigenomic dysregulation in the bone marrow mesenchymal stem cells of acquired aplastic anemia patients: An in silico and in vitro study.

چکیده اصلی

BACKGROUND: Aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome marked by pancytopenia and a hypocellular, fatty bone marrow. Growing evidence indicates that intrinsic abnormalities in bone marrow-derived mesenchymal stem cells (BM-MSCs), including inadequate hematopoietic support, cellular senescence, chronic inflammation, and enhanced adipogenic differentiation, contribute to disease pathophysiology. However, the epigenetic mechanisms underlying these abnormalities remain poorly understood. This work aims to define the epigenetic landscape of AA BM-MSCs and investigate key epigenetic regulators associated with niche failure. METHODS AND RESULTS: RNA sequencing data from AA patients and healthy controls were analyzed using bioinformatics methods, including differential gene expression analysis, Gene Ontology (GO) analysis, and Reactome pathway enrichment analysis. Principal component analysis revealed a clear separation between AA and control samples. Differential expression analysis identified 713 disrupted epigenetic regulators in AA BM-MSCs. Functional enrichment analysis indicated significant changes in pathways including chromatin remodelling, stem cell maintenance, DNA damage response, cellular senescence, inflammation, and lineage commitment. Quantitative real-time PCR validation confirmed overexpression of SETD1A, MLL1, EZH2, KDM3A, and PRMT1, and downregulation of DNMT3A, KDM2B, EHMT1, and KDM5C, consistent with the transcriptomic results. CONCLUSIONS: Our data show that AA BM-MSCs exhibit broad epigenetic dysregulation, which may contribute to bone marrow niche failure, chronic inflammation, senescence-associated changes, and reduced hematopoietic support. These findings provide novel insights into the epigenetic basis of AA pathobiology and suggest potential treatment targets to restore the function of the bone marrow microenvironment.

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