@misc{Dźwigońska_Monika_The_2025,
 author={Dźwigońska, Monika},
 editor={Leszczyńska, Katarzyna : Supervisor},
 copyright={Rights Reserved - Free Access},
 address={Warsaw},
 howpublished={online},
 year={2025},
 school={Nencki Institute of Experimental Biology PAS},
 school={degree obtained: 17.04.2026},
 publisher={Nencki Institute of Experimental Biology PAS},
 language={eng},
 abstract={Hypoxia is a common feature of solid tumours, arising from abnormal vasculature that fails to deliver sufficient oxygen to rapidly proliferating tumour cells. This physiological stress plays a pivotal role in tumour progression by contributing to genomic instability, enhancing cellular invasiveness, metastatic potential, suppressing anti-tumour immunity, and reducing the efficacy of major treatments. In IDH-wild-type glioblastoma (GBM), the most aggressive and deadly primary brain tumour, intratumoral hypoxia is highly extensive and represents a critical determinant of poor patient survival. Moreover, the GBM microenvironment is infiltrated by diverse cell types, with glioma-associated microglia and macrophages (GAMs) constituting the predominant population. These cells can adopt immunosuppressive phenotypes and are recognised as major contributors of glioma progression. Since GAMs are commonly recruited to hypoxic niches, such stress can further enhance their tumour-promoting functions. One of key cellular responses to hypoxia is the remodelling of chromatin properties through histone modifications and DNA methylation. However, the extent to which these changes contribute to the hypoxia-driven reprogramming of the GBM transcriptome is not yet fully understood. In this study, the impact of hypoxic stress on chromatin reprograming and transcriptomic profiles within the glioma TME was investigated, particularly in GAMs. First, using the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) approach, hypoxia- dependent chromatin alterations were assessed in glioma cells. The data revealed global reduction in chromatin accessibility at promoter regions of numerous genes under hypoxic condition (<0.1% O2). Notably, specific functional pathways were affected, including those involved in mRNA processing and splicing, as well as regulators of R-loop formation. Second, hypoxia was found to alter the expression of key identity marker genes in GAMs. In glioma- co-cultured GAMs in vitro and in glioblastoma patient samples, hypoxia upregulated the expression of monocytic marker Lgals3 and downregulated the homeostatic microglial markers P2ry12 and Tmem119. In addition, hypoxic stress appeared to interfere with multiple functional markers, including genes related to lipid metabolism, phagocytosis, chemotaxis, ribosomal biogenesis, and the interferon response. Some of these hypoxia-induced changes in GAMs were fine-tuned through the changes in chromatin accessibility. Furthermore, it was found that hypoxia induced lipid droplet accumulation in myeloid cells via increased expression of lipid storage-related genes and this effect could be reversed through targeting epigenetic mechanisms with histone deacetylase inhibitors. Overall, these findings highlight hypoxic stress as a potent epigenomic and transcriptomic regulator of glioma TME which may hold significance for future basic research and clinical applications.},
 title={The role of epigenetic and transcriptomic changes in the hypoxic microenvironment of glioma : PhD thesis},
 type={Text},
 URL={http://rcin.org.pl/ibd/Content/262615/PhD%20Thesis%20MDzwigonska%20final.pdf},
 keywords={Epigenetics, Glioma, Hypoxia, Lipid metabolism, Myeloid cells, Tumor microenvironment},
}