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

Abstract

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.

Keywords

Iron homeostasis / Epigenetic regulation / SETD2 / Ferritinophagy / H3K36 methylation / IRP2

Ethical statements

Not applicable.

Author contributions

The authors confirm their contributions to the commentary as follows: study conception, manuscript revision, and supervision: Zhang Y, Rouault TA; draft manuscript preparation and figure creation: Zhang Y. Both authors reviewed the results and approved the final version of the manuscript.

Data availability

Data sharing is not applicable to this commentary as no datasets were generated or analyzed.

Acknowledgments

The authors thank the Eunice Kennedy Shriver National Institute of Child Health and Human Development for support. This work was funded by the Intramural Research Program of the National Institutes of Health (1ZIA HD001602-Regulation of Intracellular Iron Metabolism).

Conflict of interest

The authors declare no conflict of interest.

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