@article{9ba7705497ba4e1381fdc028b8d57c94,
title = "In vivo CRISPR screening identifies BAZ2 chromatin remodelers as druggable regulators of mammalian liver regeneration",
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 165 chromatin regulatory proteins. Both screens identified the 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 healing 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 Rpl10a or Rpl24 was sufficient to drive regeneration, whereas 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.",
keywords = "CRISPRa, bromodomain inhibitors, chromatin remodeling, colitis, hepatocyte proliferation, in vivo CRISPR screening, inflammatory bowel disease, liver regeneration, partial hepatectomy, protein synthesis",
author = "Yuemeng Jia and Lin Li and Lin, {Yu Hsuan} and Purva Gopal and Shunli Shen and Kejin Zhou and Xueliang Yu and Tripti Sharma and Yu Zhang and Siegwart, {Daniel J.} and Ready, {Joseph M.} and Hao Zhu",
note = "Funding Information: We thank J. Xu, M. Buszczak, M. Kharas, and A. Hsieh for constructive comments; C. Lewis (UTSW Tissue Procurement Service) and J. Shelton (UTSW histopathology Core) for histopathology; and J. Xu (CRI Sequencing Core) for sequencing. H.Z. is supported by the Pollack Foundation, NIH R01 grants (DK111588, DK125396, CA251928), an Emerging Leader Award from the Mark Foundation For Cancer Research (#21-003-ELA), and a Stand Up To Cancer Innovative Research Grant (SU2C-AACR-IRG 10-16). The Zhu lab and Y.-H.L. are supported by an Innovation Award from the Moody Medical Research Institute. D.J.S. acknowledges financial support from NIH R01 EB025192-01A1 and Cancer Prevention and Research Institute of Texas (CPRIT) RP190251. J.M.R. acknowledges financial support from the Welch Foundation (I-1612). Y.J. and H.Z. conceived the project, performed the experiments, and wrote the manuscript. L.L. Y.-H.L. and S.S. performed animal and cell culture experiments. P.G. performed the histologic analysis. Y.Z. and T.S. created and analyzed the mouse models. Y.J. analyzed the genomic data. K.Z. X.Y. and D.J.S. performed the in vivo siRNA experiments. J.M.R. contributed to the writing of the paper. H.Z. has a sponsored research agreement with Alnylam Pharmaceuticals, consults for Flagship Pioneering, and serves on the SAB of Ubiquitix. These interests are not directly related to the contents of this paper. Funding Information: We thank J. Xu, M. Buszczak, M. Kharas, and A. Hsieh for constructive comments; C. Lewis (UTSW Tissue Procurement Service) and J. Shelton (UTSW histopathology Core) for histopathology; and J. Xu (CRI Sequencing Core) for sequencing. H.Z. is supported by the Pollack Foundation , NIH R01 grants ( DK111588 , DK125396 , CA251928 ), an Emerging Leader Award from the Mark Foundation For Cancer Research (# 21-003-ELA ), and a Stand Up To Cancer Innovative Research Grant ( SU2C-AACR-IRG 10-16 ). The Zhu lab and Y.-H.L. are supported by an Innovation Award from the Moody Medical Research Institute . D.J.S. acknowledges financial support from NIH R01 EB025192-01A1 and Cancer Prevention and Research Institute of Texas (CPRIT) RP190251 . J.M.R. acknowledges financial support from the Welch Foundation ( I-1612 ). Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = mar,
day = "3",
doi = "10.1016/j.stem.2022.01.001",
language = "English (US)",
volume = "29",
pages = "372--385.e8",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "3",
}