小柯机器人

美国德克萨斯大学西南医学中心Hao Zhu研究组发现，BAZ2染色质重塑因子是哺乳动物肝脏再生的可药物靶向的调节因子。该研究于2022年1月27日在线发表于国际一流学术期刊《细胞—干细胞》。

研究人员在再生肝脏中采用了汇合CRISPR敲除和激活筛选，以评估165个染色质调节蛋白。这两种筛选方法都发现了imitation-SWI的染色质重塑成分Baz2a和Baz2b，其以前没有涉及到再生。体内sgRNA、siRNA和针对任一准分子的敲除策略证实了再生的增加。不同的BAZ2特异性bromodomain抑制剂（GSK2801和BAZ2-ICR），导致不同损伤后肝脏加速愈合。抑制剂处理过的小鼠在炎症性肠病模型中也表现出更好的愈合能力，这表明多组织的适用性。再生肝脏的转录组学显示核糖体和细胞周期mRNA的增加。

令人惊讶的是，确定机制的CRISPRa筛选显示，过度产生Rpl10a或Rpl24足以驱动再生，而Rpl24单倍体不足是BAZ2抑制介导的再生的速率限制。imitation-SWI成分再生作用的发现为加强组织修复提供了直接的策略。

据介绍，由于体内筛选方法的匮乏，识别调节哺乳动物再生的新途径具有挑战性。

附：英文原文

Title: In vivo CRISPR screening identifies BAZ2 chromatin remodelers as druggable regulators of mammalian liver regeneration

Author: Yuemeng Jia, Lin Li, Yu-Hsuan Lin, Purva Gopal, Shunli Shen, Kejin Zhou, Xueliang Yu, Tripti Sharma, Yu Zhang, Daniel J. Siegwart, Joseph M. Ready, Hao Zhu

Issue&Volume: 2022-01-27

Abstract: Identifying new pathways that regulate mammalian regeneration is challenging due tothe paucity of in vivo screening approaches. We employed pooled CRISPR knockout and activation screeningin the regenerating liver to evaluate 165 chromatin regulatory proteins. Both screensidentified 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 increasedregeneration. Distinct BAZ2-specific bromodomain inhibitors, GSK2801 and BAZ2-ICR,resulted in accelerated liver healing after diverse injuries. Inhibitor-treated micealso exhibited improved healing in an inflammatory bowel disease model, suggestingmulti-tissue applicability. Transcriptomics on regenerating livers showed increasesin ribosomal and cell cycle mRNAs. Surprisingly, CRISPRa screening to define mechanismsshowed that overproducing Rpl10a or Rpl24 was sufficient to drive regeneration, whereas Rpl24 haploinsufficiency was rate limiting for BAZ2 inhibition-mediated regeneration. Thediscovery of regenerative roles for imitation-SWI components provides immediate strategiesto enhance tissue repair.

DOI: 10.1016/j.stem.2022.01.001

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00001-7

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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