Work led by Anthony Martinelli in James Nathan’s group (CITIID, Medicine), now published in Science Advances, provides the first comprehensive map of the critical genes that regulate iron within our cells.
Iron is a classic double-edged sword: essential for life, yet toxic in excess. This new map of the cell’s iron-control network, from cellular trafficking proteins to mitochondrial enzymes, opens up new avenues for exploration.
The team also identified a role for the epigenetic regulator SETD2 in influencing how cells use iron. This discovery challenges the traditional view that iron is controlled primarily after genes are transcribed. Instead, it was found that loss of SETD2 and changes in how genes are spliced can reduce a cell's ability to liberate its own iron stores.
Indeed, kidney and lung cancers with SETD2 mutations were shown to be resistant to an iron-dependent form of cell death, ferroptosis, which may help explain how these tumours can evade the immune system.
This work was supported by Wellcome Trust Fellowships and a Lister Institute Research Fellowship.
Our genome-wide screens have allowed us to not only confirm the importance of known iron-regulatory pathways and proteins, but also identify new ones like SETD2. We hope this resource will be really helpful for everyone working in iron biology - there's clearly a lot left to explore!
Anthony Martinelli
Clinical Lecturer in Respiratory Medicine