Epigenetic Crosstalk: How Metabolic and Chromatin Modifications Fine-Tune HIF Transcriptional Targets

Yfantis et al. (2023) and Zhu et al. (2022) point to a complex network of HIF-1 co-regulators and metabolic sensors (like SIRT2). This idea takes a step further by investigating how specific metabolic states (such as those induced by varying NAD+/NADH ratios, or reactive oxygen species) drive epigenetic changes—histone acetylation, methylation, or cysteine modifications—that in turn influence HIF-1’s chromatin binding and target gene selection. Using CRISPR-based epigenetic editing and state-of-the-art ChIP-seq, the project would map how these modifications shift the HIF-1 transcriptional landscape under different oxygen and metabolic conditions. This could uncover why the same HIF-1 molecule activates distinct gene sets in different contexts, with profound implications for targeting hypoxia in diseases like cancer (Qannita et al., 2024).

References:

1. Transcriptional Response to Hypoxia: The Role of HIF-1-Associated Co-Regulators. Angelos Yfantis, Ilias Mylonis, G. Chachami, M. Nikolaidis, Grigorios D. Amoutzias, E. Paraskeva, G. Simos (2023). Cells.
2. Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation. Reem Qannita, Ayah Alalami, Amani Harb, Shereen M. Aleidi, J. Taneera, Eman Abu-Gharbieh, W. El‐Huneidi, Mohamed A. Saleh, K. Alzoubi, M. Semreen, Mohammad Hudaib, Yasser K. Bustanji (2024). Pharmaceuticals.
3. Multiple Roles of SIRT2 in Regulating Physiological and Pathological Signal Transduction. Changhui Zhu, Xue Dong, Xiwei Wang, Yingying Zheng, Juanjuan Qiu, Yanling Peng, Jiajun Xu, Z. Chai, Chunyan Liu (2022). Genetics Research.