Chromatin complex dependencies reveal targeting opportunities in leukemia.
Chromatin complex dependencies reveal targeting opportunities in leukemia.
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DOI：
10.1038/s41467-023-36150-7
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发表时间：
2023-01-27
影响因子：
16.6
通讯作者：
Bernstein, Bradley E.
中科院分区：
文献类型：
--
作者：
Najm, Fadi J.;DeWeirdt, Peter;Moore, Molly M.;Bevill, Samantha M.;El Farran, Chadi A.;Macias, Kevin A.;Hegde, Mudra;Waterbury, Amanda L.;Liau, Brian B.;van Galen, Peter;Doench, John G.;Bernstein, Bradley E.
染色质调节剂在人类癌症中经常突变，并且是有吸引力的药物靶标。它们包括共享功能结构域并组装成相关多亚基复合物的不同蛋白质。为了研究这些调控因子之间的功能关系，在这里，我们应用组合CRISPR敲除（科斯）来测试白血病细胞中超过35，000个基因-基因配对，使用超过300，000个构建体的文库。表现出补偿性非致死性相互作用或协同致死性的顶部对富集了占据相同蛋白质复合物的旁系同源物和靶标。该筛选突出显示了在单一KO筛选中不明显的蛋白质复合物依赖性，例如MCM组蛋白交换、核小体重塑和脱乙酰酶（NuRD）复合物和HBO 1（KAT 7）复合物。我们探讨了两种方法NuRD复合物失活。KAT 7复合物的副作用和非副作用组合表现为协同致死，并且当与其他KAT 7复合物成员损失配对时，特异性地指定ING 5 PHD结构域作为潜在的治疗靶标。这些发现突出了组合筛选的力量，以提供机制的见解，并确定冗余网络内的治疗靶点。表观遗传调节因子是白血病潜在的治疗药物靶点。在这里，作者进行了组合CRISPR敲除，以测试白血病细胞中的基因-基因配对，以发现具有治疗潜力的补偿性非致死或协同致死组合。
Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks. Epigenetic regulators are potential therapeutic drug targets in leukemia. Here, the authors perform combinatorial CRISPR knockouts to test gene-gene pairings in leukemia cells to discover compensatory non-lethal or synergistic lethal combinations with therapeutic potential.
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影响因子：
10.5
作者：
Morgan MA;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
12.3
作者：
Dede M;McLaughlin M;Kim E;Hart T
通讯作者：
Hart T
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Au YZ;Gu M;De Braekeleer E;Gozdecka M;Aspris D;Tarumoto Y;Cooper J;Yu J;Ong SH;Chen X;Tzelepis K;Huntly BJP;Vassiliou G;Yusa K
通讯作者：
Yusa K
影响因子：
14.9
作者：
Ibn-Salem J;Muro EM;Andrade-Navarro MA
通讯作者：
Andrade-Navarro MA
影响因子：
64.8
作者：
Roadmap Epigenomics Consortium;Kundaje A;Meuleman W;Ernst J;Bilenky M;Yen A;Heravi-Moussavi A;Kheradpour P;Zhang Z;Wang J;Ziller MJ;Amin V;Whitaker JW;Schultz MD;Ward LD;Sarkar A;Quon G;Sandstrom RS;Eaton ML;Wu YC;Pfenning AR;Wang X;Claussnitzer M;Liu Y;Coarfa C;Harris RA;Shoresh N;Epstein CB;Gjoneska E;Leung D;Xie W;Hawkins RD;Lister R;Hong C;Gascard P;Mungall AJ;Moore R;Chuah E;Tam A;Canfield TK;Hansen RS;Kaul R;Sabo PJ;Bansal MS;Carles A;Dixon JR;Farh KH;Feizi S;Karlic R;Kim AR;Kulkarni A;Li D;Lowdon R;Elliott G;Mercer TR;Neph SJ;Onuchic V;Polak P;Rajagopal N;Ray P;Sallari RC;Siebenthall KT;Sinnott-Armstrong NA;Stevens M;Thurman RE;Wu J;Zhang B;Zhou X;Beaudet AE;Boyer LA;De Jager PL;Farnham PJ;Fisher SJ;Haussler D;Jones SJ;Li W;Marra MA;McManus MT;Sunyaev S;Thomson JA;Tlsty TD;Tsai LH;Wang W;Waterland RA;Zhang MQ;Chadwick LH;Bernstein BE;Costello JF;Ecker JR;Hirst M;Meissner A;Milosavljevic A;Ren B;Stamatoyannopoulos JA;Wang T;Kellis M
通讯作者：
Kellis M