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After damage to the adult mammalian central nervous system (CNS), surviving neurons have limited capacity to regenerate and restore functional connectivity. Conditional genetic deletion of  PTEN  results in robust CNS axon regrowth, while  PTEN  repression with short hairpin RNA (shRNA) improves regeneration but to a lesser extent, likely due to suboptimal  PTEN  mRNA knockdown using this approach. Here we employed the CRISPR/dCas9 system to repress  PTEN  transcription in neural cells. We targeted the  PTEN  proximal promoter and 5′ untranslated region with dCas9 fused to the repressor protein Krüppel-associated box (KRAB). dCas9-KRAB delivered in a lentiviral vector with one CRISPR guide RNA (gRNA) achieved potent and specific  PTEN  repression in human cell line models and neural cells derived from human iPSCs, and induced histone (H)3 methylation and deacetylation at the  PTEN  promoter. The dCas9-KRAB system outperformed a combination of four shRNAs targeting the  PTEN  transcript, a construct previously used in CNS injury models. The CRISPR system also worked more effectively than shRNAs for  Pten  repression in rat neural crest-derived PC-12 cells, and enhanced neurite outgrowth after nerve growth factor stimulation.  PTEN  silencing with CRISPR/dCas9 epigenetic editing may provide a new option for promoting axon regeneration and functional recovery after CNS trauma.

Transcriptional repression of PTEN in neural cells using CRISPR/dCas9 epigenetic editing