P14 | THE ROLE OF CHROMATIN REORGANIZATION IN HYPOXIA ADAPTATION

M. Cavallo¹, C. Casali¹, L. Giulini¹, A. Dia¹, D. Tunesi¹, G. Milanesi¹, G. Mazzini², M. Biggiogera¹ | ¹Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia; Italy; ²Institute of Molecular Genetics, National Research Council (IGMCNR), Pavia, Italy

The spatial organization of the cell nucleus bears functional relevance in both maintaining cellular homeostasis and facilitating pathological transformations. In response to external cues, it undergoes dynamic reorganization of chromatin architecture, causing the spatial relocalization of nucleic acids and specific proteins into defined nuclear clusters, whose stimulus-driven compartmentalization remains largely elusive. Among the various environmental stimuli capable of triggering such nuclear reorganization, oxygen availability plays a pivotal role. Recent studies have highlighted the role of hypoxia in reshaping the epigenetic landscape, suggesting that HIF-1α upregulation may drive chromatin remodelling events governing the expression of key genes^1,2. Nevertheless, the intricate dynamics of nuclear reorganization elicited by hypoxic stress remain poorly understood. Therefore, this work is aimed at investigating chromatin reorganization in mouse hepatocytes exposed to hypoxia mimicking conditions and during a subsequent reoxygenation phase. Our analyses suggest that cells adapt to hypoxic stress by reshaping the epigenetic landscape, resulting in a more accessible chromatin state that may support enhanced transcriptional activity, as indicated by the increased density of perichromatin granules (PGs). However, the highly decondensed environment may render the genome more susceptible to DSBs, potentially activating cell cycle checkpoints, as evidenced by the accumulation of hypoxic cells in G2/M phase. Notably, this arrest coincides with the clustering of subnuclear components, including PGs and RNP assemblies, which may serve as reservoirs for mature RNA and RNA-processing factors, respectively. In this context, we explored the role of the lncRNA MALAT1, which may contribute to the spatial organization of these functional nuclear assemblies. Further investigation could offer valuable insights into the intricate mechanisms of cellular adaptation to hypoxia, with significant implications for understanding tumour progression within hypoxic microenvironments.