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Status |
Public on Jan 25, 2022 |
Title |
In vivo CRISPR screening reveals druggable regulators of mammalian tissue regeneration [H2-ATAC-seq] |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
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.
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Overall design |
Examination of changes in chromatin accessbility after BAZ2 inhibition
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Contributor(s) |
Jia Y, Zhu H |
Citation(s) |
- Jia Y, Li L, Lin YH, Gopal P et al. In vivo CRISPR screening identifies BAZ2 chromatin remodelers as druggable regulators of mammalian liver regeneration. Cell Stem Cell 2022 Mar 3;29(3):372-385.e8. PMID: 35090595
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Submission date |
Sep 06, 2021 |
Last update date |
Apr 26, 2022 |
Contact name |
Hao Zhu |
E-mail(s) |
yuemeng.jia@utsouthwestern.edu
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Organization name |
UT Southwestern Medical Cetern
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Street address |
6000 Harry Hines Blvd
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City |
Dallas |
State/province |
TX |
ZIP/Postal code |
75202 |
Country |
USA |
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Platforms (1) |
GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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Samples (6)
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GSM5558371 |
H2.35 cells treated with GSK8573 - rep1 |
GSM5558372 |
H2.35 cells treated with GSK8573 - rep2 |
GSM5558373 |
H2.35 cells treated with GSK8573 - rep3 |
GSM5558374 |
H2.35 cells treated with GSK2801 - rep1 |
GSM5558375 |
H2.35 cells treated with GSK2801 - rep2 |
GSM5558376 |
H2.35 cells treated with GSK2801 - rep3 |
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This SubSeries is part of SuperSeries: |
GSE183502 |
In vivo CRISPR screening reveals druggable regulators of mammalian tissue regeneration |
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Relations |
BioProject |
PRJNA761083 |
SRA |
SRP335827 |