An iron sensor-based approach discovers a role for epigenetic regulation in iron homeostasis

Iron homeostasis is tightly regulated by systemic and intracellular pathways, yet how transcriptional programs and chromatin states contribute to the maintenance of iron availability remains poorly understood. A recent study developed an elegant tool by leveraging iron regulatory protein 2 (IRP2) as a metabolic sensor, in combination with CRISPR-based functional screening to map the regulatory landscape of cellular iron metabolism. Using this strategy, the histone methyltransferase SETD2 is identified as a chromatin-based regulator of IRP2 levels, ferritinophagy, and ferroptosis sensitivity. These findings reveal a new epigenetic layer of iron regulation, and provide a broader model for the metabolite-responsive sensors, through functional screening, to identify upstream networks and potential targetome.