Dr James Nathan, who is a member of our Cell and Molecular Biology Programme, and his research team in the Cambridge Institute for Therapeutic Immunology and Infectious Diseases (CITIID) have studied genes involved in the transcriptional response to oxygen availability.
Using a genome-wide CRISPR/Cas9 mutagenesis screen in human cells, they uncovered that the main oxygen-sensing transcription factors, the Hypoxia Inducible Factors (HIFs), recruit a histone methyltransferase, SET1B, to selectively and efficiently activate target genes.
They found that SET1B associates with chromatin in hypoxia in a HIF-dependent manner, and is itself oxygen regulated, providing new insights into how oxygen levels control epigenetic marks.
Their findings are particularly relevant to cancer biology. HIFs can promote tumour development and metastasis, by driving the expression of genes involved in metabolism, cell growth, blood vessel formation and inflammation.
Clinical trials targeting the HIF pathway in kidney cancers are already showing benefit, but it has not yet been possible to selectively target the aspects of the HIF pathway that drive cancer growth.
The research team explored the involvement of SET1B in tumour growth in kidney, lung and cervical cancer metastases models.
They discovered that depleting SET1B decreases solid-organ tumour growth, and prevents angiogenesis in the tumours, without altering other aspects of the HIF response. Targeting SET1B may therefore be a novel therapeutic approach to preventing cancer growth.
The work was led by Dr Brian Ortmann (CITIID, Department of Medicine), in collaboration with Prof Patrick Maxwell’s (CIMR, Medicine), Sir Prof Peter Ratcliffe’s (Francis Crick Institute) and Prof David Mole’s (University of Oxford) groups.
Dr James Nathan is a Reader in Respiratory Medicine and Wellcome Senior Clinical Fellow at the University of Cambridge. He is also an Honorary Consultant in Respiratory Medicine at Addenbrooke’s Hospital.
Ortmann, B.M., Burrows, N., Lobb, I.T. et al. The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes. Nat Genet (2021). https://doi.org/10.1038/s41588-021-00887-y