How do HIFs selectively activate a transcriptional response?

All organisms have evolved to sense and respond to oxygen availability in their environments, and at a cellular level oxygen sensing is mainly controlled by Hypoxia Inducible Factors (HIFs).

These transcription factors promote cell survival when oxygen is scarce by activating genes principally involved in blood vessel growth and altering metabolism. There are two main HIF isoforms, HIF-1 and HIF-2, which are widely expressed, and regulate distinct genes.

How this occurs is unclear, particularly as both forms bind the same HIF responsive elements (HREs) and can be expressed in the same cells.

To address this, the Nathan group has used genome-wide mutagenesis screens to identify genes required for the assembly of an active HIF-chromatin complex.

A top candidate in this screen is a poorly understood phosphatase, PPP4C, which has been implicated in chromatin remodelling and DNA repair.

I propose to use a combination of cell biology, biochemical and genetic approaches to understand the role of PPP4C in the HIF pathway, gain mechanistic insights into how HIFs differentially regulate their target genes, and elucidate the sequence of events leading to efficient activation of the HIF response.