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Is there potential for CRISPR epigenetic editing to improve regeneration of the central nervous system after injury?

28. May 2019

CTNR talk provided by the Translational Neurodegeneration Section "Albrecht Kossel", Dept. Neurology

Tuesday 28.05.2019, 09:30 – 10:30 Uhr
Seminar room 1.001, 1.OG, Altes Verwaltungsgebäude, Zentrum für Nervenheilkunde, Gehlsheimer Str. 20, 18147 Rostock

Speaker: Dr. Colette Moses – Post Doc, Telethon Kids Institute in Perth, Australia
Host: Prof. Dr. Dr. Andreas Hermann, Translational Neurodegeneration Section "Albrecht Kossel", Dept. Neurology

Abstract:
After damage to the adult mammalian central nervous system (CNS), surviving neurons are unable to regenerate axons to restore functional connections with their targets. Conditional deletion of phosphatase and tensin homolog (PTEN) results in robust axon regeneration in preclinical CNS injury models, and PTEN has also been repressed with short hairpin RNA (shRNA) and pharmacological inhibitors. However, we were interested in whether epigenetic editing to repress PTEN at the transcriptional level could provide an effective alternative to other methods of PTEN inhibition. The CRISPR/dCas9 system is a recently developed tool that allows efficient, programmable gene repression. We targeted the PTEN proximal promoter and 5’ untranslated region (UTR) with dCas9 fused to the repressor protein Krüppelassociated box (KRAB). dCas9-KRAB targeted to the PTEN 5’ UTR by a single CRISPR guide RNA (gRNA) strongly repressed PTEN expression in vitro, with associated changes in histone modifications at the PTEN promoter. The dCas9-KRAB system silenced PTEN to a greater extent than a combination of four shRNAs targeting the PTEN transcript, and showed no evidence of transcriptional regulation at predicted off-target gRNA binding sites. PTEN silencing with CRISPR/dCas9 epigenetic editing may eventually provide an option for promoting axon regeneration and functional recovery after CNS damage, but must first be investigated in preclinical models of CNS injury. The conclusion of this seminar will address the challenges of translating CRISPR to therapeutic applications in the CNS, and how these challenges might eventually be overcome.

Short CV:
Dr Colette Moses is a Postdoctoral Researcher specialising in CRISPR Gene Editing at the Telethon Kids Institute in Perth, Australia. Colette completed her PhD in 2018, in which she investigated genetic and epigenetic editing to treat melanoma and triple negative breast cancer, and to improve the regenerative potential of central nervous system neurons. Colette’s current research spans diverse areas, including high throughput screening with CRISPR knockout libraries, as well as CRISPR-based DNA tagging to track the dynamics of extrachromosomal oncogene amplification in live glioblastoma cells. If you would like to talk to the speaker, please get in contact with Andreas Hermann (andreas.hermann@med.uni-rostock.de).

Everybody is very welcome!