Defective post-transcriptional gene regulation Neil Renwick MD, PhD Laboratory of Translational RNA Biology Department of Pathology and Molecular Medicine SEAMO Innovation Showcase 2015

MBChB PhD FCAP MCTS K08 Path to research independence in Translational RNA Biology DTMH         Research theme: Using RNA to diagnose and treat disease

Post-transcriptional gene regulation DNA RNA PROTEIN miRNAs RBPs

miRNA gene mutations 1)miR-96-related non-syndromic hearing loss RNA-binding proteins 1)FMR1 loss of expression resulting in Fragile X Syndrome 2)RBM20-related Dilated Cardiomyopathy 3)RBM10-related Cleft Palate 4)TDP43-related Amyotrophic Lateral Sclerosis 5)FUS-related Amyotrophic Lateral Sclerosis RNAs 1) Likely many TBD Post-transcriptional diseases

Post-transcriptional gene regulation DNA RNA PROTEIN miRNAs RBPs

5 ng - (or less)

sequence annotation and analysis upload sequence file on RNAworld (300 mio reads) barcode extraction (20 x 15 mio reads, validated) small RNA annotation (iterative process) miRNAs 13,300,000 (88.2%) none 298,000 (2.0%) rRNA 382,000 (2.5%) snoRNA 161,048 (1.1%) std cali 254,941 (1.7%) tRNA 218,229 (1.3%) clustering, heat map (log2 expression) differential expression discriminant analysis

Post-transcriptional gene regulation DNA RNA PROTEIN miRNAs RBPs

Illustration of PAR-CLIP method 4-thiouridine

TDP-43 PAR-CLIP

Projects 1)miRNA reannotation (other RNAs) 2)miRNA-based diagnostics for NETs (cancer biology) 3)RBP pathomechanisms (TDP-43) 4)Rare disease genetics (RNA-based mutation identification) Yrs 1-2 Set up functional laboratory and recruit Obtain preliminary funding Write first and senior author manuscripts Talk to senior investigators Yrs 3-5 Develop collaborations (models) Present nationally Select topic for larger research award application Directions and plan

Lab members Xiaojing Yang (research associate) Kathrin Tyryshkin (data analyst) Bryony Dorrington (path 499 student) Betty Li (path 499 student) Tiandra Ceyhan (summer student) Dakota Gustafson (summer student) Shane Mooney (summer student) Francine Milone (volunteer) Collaborators Thomas Tuschl, The Rockefeller University (RNA biology) Yao-Tseng Chen, Weill Cornell Medical College (rare tumors) Lev Goldfarb, National Institutes of Health (genetics) Fyodor Platonov, North-Eastern Federal University (rare diseases) Andrew Craig, Queen’s University (cancer biology) Acknowledgments

Start up Department of Pathology and Molecular Medicine QU School of Medicine SEAMO Competitive AHSC AFP Innovation Fund CFI JELF MRI ORF-RI Program QU KGH Clare Nelson Bequest Fund QU SARC Grant SFARI Funding