Investigating the role of AP-1 in the transcriptional regulation of hypoxic cell adaptation

The majority of hypoxic research has focused on HIF1alpha and HIF2alpha, transcription factors (TFs) which are stabilised in hypoxia. Data suggests that the transcriptomic changes that occur are regulated by a number of TFs and epigenetic regulators. Our evidence suggests that the AP-1 transcription factors (a heterodimer of proteins from c-FOS, c-JUN and ATF proteins) are key regulators of hypoxic molecular adaptation.
We plan to test the hypothesis that novel downstream targets of the AP-1 transcription factor are activated in response to hypoxia and regulate key aspects of molecular adaptation to hypoxia.

We will:

1. Identify novel targets of AP-1 in hypoxia based on in-house RNA-SEQ data and ChIP-SEQ.
2. Validate the activation of targets in hypoxia and confirm direct activation by AP-1.
3. Identify the role of novel AP-1 targetas in molecular adaptation to hypoxia.
4. Investigate phenotypic effects of novel AP-1 pathways in cancer cells.
5. Identify HIF-independent hypoxic regulation of novel AP-1 targets using CRISPR-generated knockout lines.


Further to the skills developed in the lab rotation the student will utilise
lentiviral-shRNA/CRISPR to analyse the phenotypic effects on cancer cells including stem cell capacity angiogenesis, proliferation, 3 Dimensional culture and immunohistochemistry.
The student will with support undertake bioinformatics analyses of in house RNA-SEQ data and publically available data from The Cancer Genome Atlas.