Photo by: Nasimudeen, R. from Wikimedia Commons / 2017
Climbing a mountain and being hospitalised with severe lung disease both have similar effects on your immunity. Scientists from the University of Edinburgh have discovered that low blood oxygen levels (hypoxemia) can trigger a change in the genetic programming of the immune system, making key immune cells less effective.
To investigate, researchers analysed blood samples from two groups. One included patients who had experienced Acute Respiratory Distress Syndrome (ARDS), a condition that develops in some serious cases of COVID, and causes severe lung swelling and inflammation. The other group was healthy volunteers who spent a week at high altitude on Huayna Potosi in Bolivia. There, they experienced altitude-induced hypoxemia, a condition that people develop at high altitudes as oxygen levels drop. After running analyses, the scientists discovered that both groups showed weakened neutrophil function months after oxygen levels had returned to normal. This suggested that low oxygen alone was enough to trigger these changes.
Neutrophils are the most abundant type of white blood cell. Produced in the bone marrow, they protect the body from microbes and act as the first line of defence against infections. Because of this, they don’t live very long, usually from a couple of hours to a day. In a single day, the body produces over 100 billion new neutrophils to replace those that die.
Even though no knowledge exchange happens between old and new neutrophils, the scientists saw that the abnormalities in neutrophil function persisted for months. Hence, they concluded the changes must have been programmed at the genetic level.
Using mouse models, the team discovered that hypoxia induced an adaptive response that altered the packaging of DNA in neutrophil genes. After hypoxia, histones responsible for controlling this packaging no longer behaved the way they were supposed to.
Histones are proteins that provide structure to DNA. DNA winds around histones like thread on bobbins, folding itself in a predictable pattern. Histones also serve as communication hubs for cell machinery. Histones have tails that stick out and allow the regulation of nearby genes. A chemical marker placed on a histone tail can tell the cell’s machinery to copy the nearby gene. Another modification can tell it to stay away.
Before hypoxia, the tail close to the neutrophil genes had an important histone modification marker, called H3K4me3 (histone 3 lysine 4 trimethylation). H3K4me3 is a histone modification that we commonly see near active genes. However, after hypoxia, the histone tail holding that mark was clipped off. When the tail was gone, so was the marker. Without that mark, the genes neutrophils need to function properly became less active, making neutrophils less effective.
While these findings shed light on persistent immune weakness seen in severe COVID-19, the scientists also highlight the research’s relevance for a spectrum of chronic inflammatory conditions that affect neutrophils, such as Chronic Obstructive Pulmonary Disease (COPD).
Looking ahead, the team plans to determine whether these immune changes can be reversed. The scientists believe their research could show “new ways to think about treating long-term immune dysfunction and improve infection defences” in the long run. Treatments such as histone-marker-regenerating therapy could one day help restore neutrophil function in people suffering from long-COVID, rebuilding their immunity.
Article written by Dasha Sokol, a Science Communications master’s student at the University of Sheffield with a background in neuroscience and pharmacology.
Article edited by Priscilla Wong, a Fourth-Year Biological Sciences (Immunology) student at the University of Edinburgh, and an Online News Editor for EUSci.
Resources:
ARDS. Mayo Clinic. Retrieved Nov.4, 2025 from https://www.mayoclinic.org/diseases-conditions/ards/symptoms-causes/syc-20355576
Charlesworth, T. (2024). How histone modifications impact gene regulation. Biomodal. Retrieved Nov.4, 2025 from https://biomodal.com/blog/how-histone-modifications-impact-gene-regulation/
Eissenberg, J. C., & Shilatifard, A. (2010). Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Developmental biology, 339(2), 240–249. https://doi.org/10.1016/j.ydbio.2009.08.017
Neutrophils. Cleveland Clinic. Retrieved Nov.4, 2025 from https://my.clevelandclinic.org/health/body/22313-neutrophils
Nasimudeen, R. (2017). Neutrophil 1 [Photograph]. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Neutrophil_1.jpg
Oxygen loss raises disease risk by altering genes. (2025). The University of Edinburgh. News. Retrieved Nov.4, 2025 from https://www.ed.ac.uk/news/oxygen-loss-raises-disease-risk-by-altering-genes
Sanchez-Garcia, M. A., Sadiku, P., Ortmann, B. M., Wit, N., Negishi, Y., Coelho, P., Zhang, A., Pednekar, C., Howden, A. J. M., Griffith, D. M., Seear, R., Kindrick, J. D., Mengede, J., Cooper, G., Morrison, T., Watts, E. R., Shimeld, B. T., Reyes, L., Mirchandani, A. S., Arienti, S., … & Walmsley, S. R. (2025). Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity. Nature immunology, 26(11), 1903–1915. https://doi.org/10.1038/s41590-025-02301-9
Walvekar, K.P., & Chilaka, S.(2025). H3K4me3 is a post-transcriptional histone mark. bioRxiv, Article 2025.07.03.662929; doi: https://doi.org/10.1101/2025.07.03.662929
Zhang, F., Xia, Y., Su, J., Quan, F., Zhou, H., Li, Q., Feng, Q., Lin, C., Wang, D., & Jiang, Z. (2024). Neutrophil diversity and function in health and disease. Signal transduction and targeted therapy, 9(1), 343. https://doi.org/10.1038/s41392-024-02049-y
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