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In vivo CRISPR screening reveals druggable regulators of mammalian tissue regeneration [liver-RNA-seq]

ABSTRACT: Identifying new pathways that regulate mammalian regeneration is challenging due to the paucity of in vivo screening approaches. We employed pooled CRISPR knockout and activation screening in the regenerating liver to evaluate 164 chromatin regulatory proteins. Both screens identified imitation-SWI chromatin remodeling components Baz2a and Baz2b, not previously implicated in regeneration. In vivo sgRNA, siRNA, and knockout strategies against either paralog confirmed increased regeneration. Distinct BAZ2-specific bromodomain inhibitors GSK2801 and BAZ2-ICR resulted in accelerated liver healing after diverse injuries. Inhibitor treated mice also exhibited improved regeneration in an inflammatory bowel disease model, suggesting multi-tissue applicability. Transcriptomics on regenerating livers showed increases in ribosomal and cell cycle mRNAs. Surprisingly, CRISPRa screening to define mechanisms showed that overproducing ribosomal proteins was sufficient to drive regeneration, while Rpl24 haploinsufficiency was rate limiting for BAZ2 inhibition mediated regeneration. The discovery of regenerative roles for imitation-SWI components provides immediate strategies to enhance tissue repair.

ORGANISM(S): Mus musculus

PROVIDER: GSE183501 | GEO | 2022/01/25

REPOSITORIES: GEO

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