Philipp Markolin, PhD
The universe probably does not care, it is just us, creatures come about by a random process who developed these weird prediction machines called brains who try to infer any meaning where there is none.
- philipp.markolin@ biol.ethz.ch
Experimental Biologist turned to machines
Abstract Intra-tumor hypoxia is a common feature in many solid cancers. Although transcriptional targets of hypoxia-inducible factors (HIFs) have been well characterized, alternative splicing or processing of pre-mRNA transcripts which occurs during hypoxia and subsequent HIF stabilization is much less understood. Here, we identify HIF-dependent alternative splicing events after whole transcriptome sequencing in pancreatic cancer cells exposed to hypoxia with and without downregulation of the aryl hydrocarbon receptor nuclear translocator (ARNT), a protein required for HIFs to form a transcriptionally active dimer. We correlate the discovered hypoxia-driven events with available sequencing data from pan-cancer TCGA patient cohorts to select a narrow set of putative biologically relevant splice events for experimental validation. We validate a small set of candidate HIF-dependent alternative splicing events in multiple human cancer cell lines as well as patient-derived human pancreatic cancer organoids. Lastly, we report the discovery of a HIF-dependent mechanism to produce a hypoxia-dependent, long and coding isoform of the UDP-N-acetylglucosamine transporter SLC35A3.
Authors Philipp Markolin, Natalie R Davidson, Christian K. Hirt, Christophe D. Chabbert, Nicola Zamboni, Gerald Schwank, Wilhelm Krek, Gunnar Rätsch