Hypoxia Impacts Histone Modifications in Immune Cells

Hypoxia, or reduced oxygen availability, influences immune cell function and contributes to pathologies such as cancer and lung disease. This study investigates how hypoxia impacts global histone modification patterns and the expression of histone-modifying enzymes in peripheral immune cells. Histone modifications, including methylation and acetylation, play a key role in rapid cellular responses to stress by regulating rates of gene expression. Therefore, we hypothesized that hypoxic stress induces (1) differential expression of histone-modifying enzyme genes and (2) significant changes in global histone modification levels, particularly those linked to transcriptional repression for energy conservation. Using RNA-sequencing, [1] [2] we analyzed blood samples from 15 healthy individuals at sea level and during 3 days of high-altitude hypoxia (3800 m). We identified significant changes in histone-modifying enzyme gene expression, including decreased HDAC1 (HA1: -0.29; HA3: -0.46, p<0.001) and HDAC3 (HA1: -0.34; HA3: -0.48, p<0.001), and increased KDM3A (HA1: 0.28; HA3: 0.12) and SIRT1 (HA1: 0.43; HA3: 0.27). In addition, we cultured peripheral immune cells in hypoxia (1% O2) and identified increased levels of the histone modifications H3K9me3, H3K36me3, H3K79me3, and H3K2me3. These findings suggest histone modifications are significantly altered by hypoxic cell stress and may play a critical role in rapid cellular adaptation to oxygen limitation. Future work will map genomic locations of these modifications to uncover mechanisms driving cellular and physiological responses to hypoxic stress.