清脆的
表观遗传学
基因组编辑
生物
重编程
Cas9
计算生物学
CRISPR干扰
表观基因组
基因组工程
组蛋白
基因
细胞生物学
遗传学
DNA甲基化
基因表达
作者
Yiqian Wu,Ziliang Huang,Yahan Liu,Charles H. Yoon,Kun Sun,Yinglin Situ,Phuong N. Ho,Yuan Zhou,Linshan Zhu,Justin Eyquem,Yunde Zhao,Thomas T. Liu,Gabriel A. Kwong,Shu Chien,Yingxiao Wang
标识
DOI:10.1101/2023.06.21.544125
摘要
Abstract CRISPR (clustered regularly interspaced short palindromic repeats) is a revolutionary technology for genome editing. Its derived technologies such as CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) further allow transcriptional and epigenetic modulations. Focused ultrasound (FUS) can penetrate deep in biological tissues and induce mild hyperthermia in a confined region to activate heat-sensitive genes. Here we engineer a set of CRISPR(a/i) tools containing heat-sensitive genetic modules controllable by FUS for the regulation of genome and epigenome in live cells and animals. We demonstrated the capabilities of FUS-inducible CRISPRa, CRISPRi, and CRISPR (FUS-CRISPR(a/i)) to upregulate, repress, and knockout exogenous and/or endogenous genes, respectively, in different cell types. We further targeted FUS-CRISPR to telomeres in tumor cells to induce telomere disruption, inhibiting tumor growth and enhancing tumor susceptibility to killing by chimeric antigen receptor (CAR)-T cells. FUS-CRISPR-mediated telomere disruption for tumor priming combined with CAR-T therapy demonstrated synergistic therapeutic effects in xenograft mouse models. The FUS-CRISPR(a/i) toolbox allows the remote, noninvasive, and spatiotemporal control of genomic and epigenomic reprogramming in vivo, with extended applications in cancer treatment.
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