An Integrated Genome-wide CRISPRa Approach to Functionalize lncRNAs in Drug Resistance.
An Integrated Genome-wide CRISPRa Approach to Functionalize lncRNAs in Drug Resistance.
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DOI：
10.1016/j.cell.2018.03.052
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发表时间：
2018-04-19
期刊：
影响因子：
64.5
通讯作者：
Pandolfi PP
中科院分区：
文献类型：
--
作者：
Bester AC;Lee JD;Chavez A;Lee YR;Nachmani D;Vora S;Victor J;Sauvageau M;Monteleone E;Rinn JL;Provero P;Church GM;Clohessy JG;Pandolfi PP
对化疗的抵抗在癌症死亡率中起着重要作用。为了确定影响阿糖胞苷(AML)治疗的主要药物阿糖胞苷敏感性的遗传单位，我们开发了一个基于双重蛋白质编码和非编码集成CRISPRa筛选(DICAS)的全面、集成的全基因组平台。最初使用来自517个人类泛癌细胞系的药物遗传学数据鉴定了可能的耐药基因。随后，通过CRISPR激活对编码基因和lncRNA基因进行了基因组规模的功能表征。为了评估lncRNA的功能，我们开发了一种CRISPR激活lncRNA(CALR)策略，针对14,701个lncRNA基因。计算和功能分析发现了新的细胞周期调控、生存/凋亡和癌症信号基因。此外，我们分析中发现的Gas6-AS2lncRNA的转录激活导致Gas6/途径的过度激活，这是包括急性髓细胞白血病在内的多种癌症的一种耐药机制。因此，DICAS代表了一种新的和强大的方法来识别与治疗相关的整合的编码和非编码途径。CRISPR激活屏幕识别与化疗耐药有关的编码和非编码途径
Resistance to chemotherapy plays a significant role in cancer mortality. To identify genetic units affecting sensitivity to cytarabine, the mainstay of treatment for AML, we developed a comprehensive and integrated genome wide platform based on a Dual protein-coding and noncoding Integrated CRISPRa Screening (DICaS). Putative resistance genes were initially identified using pharmacogenetic data from 517 human pan-cancer cell lines. Subsequently, genome scale functional characterization of both coding and lncRNA genes by CRISPR activation was performed. For lncRNA functional assessment we developed a CRISPR activation of lncRNA (CaLR) strategy, targeting 14,701 lncRNA genes. Computational and functional analysis identified novel cell cycle regulation, survival/apoptosis, and cancer signaling genes. Furthermore, transcriptional activation of the GAS6-AS2 lncRNA, identified in our analysis, leads to hyperactivation of the GAS6/TAM pathway, a resistance mechanism in multiple cancers, including AML. Thus, DICaS represents a novel and powerful approach to identify integrated coding and non-coding pathways of therapeutic relevance. A CRISPR activation screen identifies both coding and noncoding pathways involved in resistance to chemotherapy
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影响因子：
48
作者：
Chavez A;Tuttle M;Pruitt BW;Ewen-Campen B;Chari R;Ter-Ovanesyan D;Haque SJ;Cecchi RJ;Kowal EJK;Buchthal J;Housden BE;Perrimon N;Collins JJ;Church G
通讯作者：
Church G
DOI：
10.1158/1078-0432.ccr-12-3066
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cheng Z;Gong Y;Ma Y;Lu K;Lu X;Pierce LA;Thompson RC;Muller S;Knapp S;Wang J
通讯作者：
Wang J
影响因子：
64.5
作者：
Basu A;Bodycombe NE;Cheah JH;Price EV;Liu K;Schaefer GI;Ebright RY;Stewart ML;Ito D;Wang S;Bracha AL;Liefeld T;Wawer M;Gilbert JC;Wilson AJ;Stransky N;Kryukov GV;Dancik V;Barretina J;Garraway LA;Hon CS;Munoz B;Bittker JA;Stockwell BR;Khabele D;Stern AM;Clemons PA;Shamji AF;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H