Cells starved of oxygen switch on a master protein called HIF to survive, but this same response fuels cancer and inflammatory diseases—and drugs that block HIF directly risk poisoning healthy tissue. The problem is that HIF has no obvious pocket for a drug to latch onto, and shutting it down entirely causes toxic side effects. This project tackles that gap by targeting not HIF itself, but the enzymes that control which genes HIF switches on. The researcher recently discovered that a methylation enzyme called SET1B fine-tunes HIF’s activity in immune cells, opening a more precise way to dial HIF up or down depending on the disease. If successful, this work could lead to therapies that curb runaway inflammation in arthritis or colitis, or starve tumours of their oxygen supply, without the collateral damage of broad HIF inhibition. It also maps a largely unknown landscape of methylation changes that orchestrate the entire oxygen-stress response. This is fundamental science. The immediate payoff is a deeper understanding of how cells coordinate survival under low oxygen—knowledge that could eventually guide drug development for conditions where oxygen supply goes wrong, from heart attacks to chronic lung disease.
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The cellular response to hypoxia (low oxygen) is crucial for survival, with the transcription factor HIF (HIF-1 and HIF-2), playing a central role in this adaptive process. Hypoxia and HIF activation are prominent in inflammatory diseases and cancer, prompting interest in targeting hypoxia and HIF for therapy. However, direct HIF targeting poses challenges due to its lack of an active site and potential toxicity. My research plans aim to explore a novel therapeutic strategy to solve the problem of targeting HIF. Our recent research identified SET1B, a histone methyltransferase, as a pivotal regulator of HIF transcriptional specificity, opening a new paradigm for more precise modulation of HIF activity by targeting epigenetic regulators. This approach holds significant clinical promise, enabling targeted HIF modulation across different disease and immune contexts, while mitigating broad HIF inhibition-associated toxicity. SET1B is just one member of a broader methylase family, whose function(s) in hypoxia is unknown. Furthermore, several demethylases' activities are oxygen-regulated and are direct HIF targets, suggesting that changes in methylation dynamics govern cellular function in hypoxia. I hypothesise that methylation of key regulatory proteins is dynamically regulated in hypoxia and is crucial for coordinating the cellular response. Using SET1B as an entry point, we will use genetic screening, proteomics, and cell biology to elucidate the biological role of methylation in the coordination of the hypoxia response. Given the current focus on targeting lysine and arginine methylation therapeutically, this research has the potential to have significant clinical impact in diseases associated with hypoxia.
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