Poster Presentation 39th Annual Lorne Genome Conference 2018

Metabolic and transcriptomic analyses of Müller glial cells of the retina (#172)

Thaksaon Kittipassorn 1 2 , Cameron D. Haydinger 1 , John P. Wood 3 4 , Teresa Mammone 3 4 , Robert J. Casson 3 4 , Daniel J. Peet 1
  1. Department of Molecular & Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
  2. Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
  3. Ophthalmic Research Laboratories, Hanson Institute, Adelaide, SA, Australia
  4. South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, SA, Australia

The glycolytic enzyme pyruvate kinase M2 (PKM2) is a target gene of the transcription factor hypoxia inducible factor-1 (HIF-1), and in turn acts as a coactivator for HIF-1 in cancer cells. PKM2 enhances DNA binding and coactivator recruitment to hypoxia response elements of HIF-1 target genes, increasing transcription. This leads to various cellular responses including upregulation of glycolysis. Together PKM2 and HIF-1 have been implicated in driving aerobic glycolysis (also known as the Warburg effect) in cancer and other proliferating cells. Surprisingly the non-proliferating mammalian retina also displays the Warburg effect. We hypothesise that PKM2 and HIF-1 influence metabolic gene transcription and drive the Warburg effect in the retina, similar to cancer. Here we show PKM2 and HIF-1 expression in Müller glial cells of the retina, and demonstrate that the retina in vivo expresses PKM2 [1]. We investigate the role of PKM2 in cellular metabolism and metabolic gene expression in Müller cells, using in vitro knockdown and CRISPR/Cas9-mediated knockout models. To facilitate studies of Müller cells, we have generated a novel spontaneously immortalised rat Müller cell line SIRMu-1. We profile the transcriptome of these cells by RNA sequencing and compare this to primary Müller cells and the SV40-immortalised Müller cell line rMC-1. We also report bioinformatic analysis of the differential expression of metabolic genes among retinal cell types from published single-cell RNA sequencing data. Understanding the molecular basis of transcriptional control of retinal metabolism may aid diagnosis and treatment of retinal diseases. Additionally, if mechanisms underlying the Warburg effect in cancer and the retina are conserved, caution needs to be exercised when designing novel cancer treatments targeting aerobic glycolysis as they may also damage the retina.

  1. [1] Casson R.J., Wood J.P., Han G., Kittipassorn T., Peet D.J., Chidlow G. (2016) Invest. Ophthalmol. Vis. Sci. 57(1):66-80.