Jianli Yin, Hang Wan, Deqiang Kong, Xingwan Liu, Ying Guan, Jiali Wu, Yang Zhou, Xiaoding Ma, Chunbo Lou, Haifeng Ye, Ningzi Guan
{"title":"基于 CRISPR-dCas9 的数字化基因重塑生物计算机,由哺乳动物体内的膳食化合物编程。","authors":"Jianli Yin, Hang Wan, Deqiang Kong, Xingwan Liu, Ying Guan, Jiali Wu, Yang Zhou, Xiaoding Ma, Chunbo Lou, Haifeng Ye, Ningzi Guan","doi":"10.1016/j.cels.2024.09.002","DOIUrl":null,"url":null,"abstract":"<p><p>CRISPR-dCas9 (dead Cas9 protein) technology, combined with chemical molecules and light-triggered genetic switches, offers customizable control over gene perturbation. However, these simple ON/OFF switches cannot precisely determine the sophisticated perturbation process. Here, we developed a resveratrol and protocatechuic acid-programmed CRISPR-mediated gene remodeling biocomputer (REPA<sub>CRISPR</sub>) for conditional endogenous transcriptional regulation of genes in vitro and in vivo. Two REPA<sub>CRISPR</sub> variants, REPA<sub>CRISPRi</sub> and REPA<sub>CRISPRa</sub>, were designed for the logic control of gene inhibition and activation, respectively. We successfully demonstrated the digital computations of single or multiplexed endogenous gene transcription by using REPA<sub>CRISPRa</sub>. We also established mathematical models to predict the dose-responsive transcriptional levels of a target endogenous gene controlled by REPA<sub>CRISPRa</sub>. Moreover, high levels of endogenous gene activation in mice mediated by the AND logic gate demonstrated computational control of CRISPR-dCas9-based epigenome remodeling in mice. This CRISPR-based biocomputer expands the synthetic biology toolbox and can potentially advance gene-based precision medicine. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"941-955.e5"},"PeriodicalIF":0.0000,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A digital CRISPR-dCas9-based gene remodeling biocomputer programmed by dietary compounds in mammals.\",\"authors\":\"Jianli Yin, Hang Wan, Deqiang Kong, Xingwan Liu, Ying Guan, Jiali Wu, Yang Zhou, Xiaoding Ma, Chunbo Lou, Haifeng Ye, Ningzi Guan\",\"doi\":\"10.1016/j.cels.2024.09.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>CRISPR-dCas9 (dead Cas9 protein) technology, combined with chemical molecules and light-triggered genetic switches, offers customizable control over gene perturbation. However, these simple ON/OFF switches cannot precisely determine the sophisticated perturbation process. Here, we developed a resveratrol and protocatechuic acid-programmed CRISPR-mediated gene remodeling biocomputer (REPA<sub>CRISPR</sub>) for conditional endogenous transcriptional regulation of genes in vitro and in vivo. Two REPA<sub>CRISPR</sub> variants, REPA<sub>CRISPRi</sub> and REPA<sub>CRISPRa</sub>, were designed for the logic control of gene inhibition and activation, respectively. We successfully demonstrated the digital computations of single or multiplexed endogenous gene transcription by using REPA<sub>CRISPRa</sub>. We also established mathematical models to predict the dose-responsive transcriptional levels of a target endogenous gene controlled by REPA<sub>CRISPRa</sub>. Moreover, high levels of endogenous gene activation in mice mediated by the AND logic gate demonstrated computational control of CRISPR-dCas9-based epigenome remodeling in mice. This CRISPR-based biocomputer expands the synthetic biology toolbox and can potentially advance gene-based precision medicine. A record of this paper's transparent peer review process is included in the supplemental information.</p>\",\"PeriodicalId\":93929,\"journal\":{\"name\":\"Cell systems\",\"volume\":\" \",\"pages\":\"941-955.e5\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-10-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell systems\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cels.2024.09.002\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/9 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell systems","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.cels.2024.09.002","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/9 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
A digital CRISPR-dCas9-based gene remodeling biocomputer programmed by dietary compounds in mammals.
CRISPR-dCas9 (dead Cas9 protein) technology, combined with chemical molecules and light-triggered genetic switches, offers customizable control over gene perturbation. However, these simple ON/OFF switches cannot precisely determine the sophisticated perturbation process. Here, we developed a resveratrol and protocatechuic acid-programmed CRISPR-mediated gene remodeling biocomputer (REPACRISPR) for conditional endogenous transcriptional regulation of genes in vitro and in vivo. Two REPACRISPR variants, REPACRISPRi and REPACRISPRa, were designed for the logic control of gene inhibition and activation, respectively. We successfully demonstrated the digital computations of single or multiplexed endogenous gene transcription by using REPACRISPRa. We also established mathematical models to predict the dose-responsive transcriptional levels of a target endogenous gene controlled by REPACRISPRa. Moreover, high levels of endogenous gene activation in mice mediated by the AND logic gate demonstrated computational control of CRISPR-dCas9-based epigenome remodeling in mice. This CRISPR-based biocomputer expands the synthetic biology toolbox and can potentially advance gene-based precision medicine. A record of this paper's transparent peer review process is included in the supplemental information.