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MESC histone modifications under normoxia and hypoxia

ABSTRACT: The physiological behavior of mouse embryonic stem cells (mESCs) is intricately regulated by microenvironmental oxygen levels, with normoxia (21% O₂) and hypoxia (1-5% O₂) exhibiting distinct impacts on self-renewal, differentiation, and metabolic adaptation. However, the epigenetic mechanisms underlying oxygen-dependent gene expression remain poorly characterized. This study investigates the dynamic alterations of histone modifications associated with transcriptional regulation—specifically, the active promoter mark H3K4me3 (trimethylation of histone H3 lysine 4) and the enhancer mark H3K27ac (acetylation of histone H3 lysine 27)—in mESCs under normoxic versus hypoxic conditions. Utilizing chromatin immunoprecipitation followed by sequencing (ChIP-seq), we systematically mapped genome-wide occupancy patterns of H3K4me3 and H3K27ac, identifying oxygen-sensitive epigenetic landscapes that correlate with differential gene activity. Comparative analysis revealed hypoxia-induced redistribution of these marks at loci linked to pluripotency maintenance, hypoxia-responsive pathways (e.g., HIF-1α targets), and metabolic reprogramming. These findings highlight the role of oxygen tension in reshaping the epigenetic architecture of mESCs, providing insights into how microenvironmental cues fine-tune stem cell functionality through histone modification dynamics. This work advances our understanding of epigenetic plasticity in stem cells and may inform strategies for optimizing in vitro culture conditions or manipulating cell fate under physiological or pathological oxygen gradients.

ORGANISM(S): Mus musculus

PROVIDER: GSE294812 | GEO | 2025/07/23

REPOSITORIES: GEO

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Project description:Hypoxia in stem cell niches and inner core of solid tumors contributes to cellular senescence and differentiation inhibition. It directly increases histone methylationby inhibiting the activities of O2-and α-ketoglutarate (α-KG)-dependent histone lysine demethylases. This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping and heterochromatin redistribution, named senescence-associated heterochromatin foci (SAHF), which are found during oncogene-induced senescence (OIS). This study showed that Raf activation in primary human fibroblasts IMR90 increases mature cathepsin L (CTSL)-mediated cleavage of H3, H2B, and H4. Hypoxia prevented H3 cleavage not by inhibiting CTSL but by increasing H3K18me3 and H3K23me3 nearby cleaved site of H3. Forced expression of cleaved H3 in IMR90 cells induced senescence even under hypoxia, suggesting that hypoxia breaks this positive feedback senescence driving circle by increasing methylated histones. The decrease in methylated histones is necessary for OIS to trigger histone clipping and SAHFs, but hypoxia maintains methylated histones to prevent both. Forced reduction of methylated histones in hypoxic cells using inhibitors of methyl-transferases makes hypoxic conditions unable to prevent OIS from inducing both histone clipping and SAHFs. Reversely forced enhancement of methylated histones in normoxic cells using inhibitors of histone demethylases protected histones from clipping during OIS but failed to block SAHFs. Altogether, the maintenance of methylated histones, especially H3K23me3 and H3K18me3, is sufficient to protect histones from clipping during OIS, but not for inhibiting SAHFs, suggesting that besides inhibiting KDMs, hypoxia adopts other methods to inhibit SAHFs. These findings provide a novel mechanism by which hypoxia affects cell fate by increasing methylated histones that protect histones and chromatin from dramatic epigenetic changes.

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MESC histone modifications under normoxia and hypoxia

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