Poster Presentation 16th Asian Conference on Transcription 2019

Drosophila models reveal FUBP1 and CIC, predicted oligodendroglioma driver mutations, inhibit expansion of the neural stem cell lineage in vivo (1160)

Nan-Hee Kim 1 , Olga Zaytseva 1 2 , Naomi Mitchell 1 2 , Caroline Delandre 3 , Mark Gilbert 4 , David Levens 4 , Owen Marshall 3 , Leonie Quinn 1 2
  1. Department of Cancer Biology and Therapeutics, The Australian National University, Canberra, ACT, Australia
  2. The University of Melbourne, Melbourne, VIC, Australia
  3. Menzies Institute for Medical Research, Hobart, TAS, Australia
  4. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

FUBP1, a single stranded DNA/RNA binding protein, was initially characterised as a transcriptional activator of the MYC oncogene and thus driver of cell growth and proliferation. Genome sequencing in oligodendroglioma, however, identified putative loss-of-function FUBP1mutations as tumour drivers, suggesting that FUBP1 behaves as a tumour suppressor in the context of the brain. Exciting preliminary data demonstrate FUBP1/Psi knockdown specifically in the neural stem cells drives lineage expansion, consistent with tumour suppressor function in oligodendroglioma. Not only were genes controlling neural stem cell lineage maintenance and proliferation identified as direct FUBP1/Psi targets using Targeted DamID (TaDa), but analysis of TCGA data revealed 72% of the human orthologs of the Drosophila targets were dysregulated in low grade glioma. As FUBP1 mutations significantly co-occur with loss-of-function mutations in the CIC transcriptional repressor of receptor tyrosine kinase signalling, we are testing whether expansion of the neural stem cell lineage driven by FUBP1/Psi knockdown is modified by concurrent CIC/cic knockdown. We will further investigate genome wide CIC binding in the stem cell lineage, correlate with active and inactive chromatin state, and determine whether CIC binding is modified by Psi abundance (and vice versa). Thus we will determine how FUBP1/Psi and CIC interact to control neural stem cell fate in Drosophila, providing in vivo insight into how loss-of-function for the FUBP1 and CIC transcriptional regulators drives oligodendroglioma.