In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis.
In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis.
复制标题
DOI：
10.1038/s41588-023-01471-2
复制
发表时间：
2023-09
期刊：
影响因子：
30.8
通讯作者：
Huntly, Brian J. P.
中科院分区：
文献类型：
--
作者：
Lara-Astiaso, David;Goni-Salaverri, Ainhoa;Mendieta-Esteban, Julen;Narayan, Nisha;Del Valle, Cynthia;Gross, Torsten;Giotopoulos, George;Beinortas, Tumas;Navarro-Alonso, Mar;Aguado-Alvaro, Laura Pilar;Zazpe, Jon;Marchese, Francesco;Torrea, Natalia;Calvo, Isabel A.;Lopez, Cecile K.;Alignani, Diego;Lopez, Aitziber;Saez, Borja;Taylor-King, Jake P.;Prosper, Felipe;Fortelny, Nikolaus;Huntly, Brian J. P.
细胞分化需要染色质结构和功能的广泛改变，这是由染色质和转录因子的协调作用引起的。与转录因子相比，染色质因子在分化中的作用尚未得到系统的表征。在这里，我们结合联合收割机批量离体和单细胞体内CRISPR筛选来表征染色质因子家族在造血中的作用。我们发现了142个染色质因子的显着谱系特异性，揭示了相关染色质因子（即自整合障碍因子亚复合物）之间的功能多样性，以及抑制过度骨髓分化的不相关抑制复合物的共同作用。使用表观遗传分析，我们确定谱系决定转录因子和几个染色质因子，解释他们的谱系依赖性之间的功能相互作用。研究白血病中的染色质因子功能，我们表明白血病细胞利用稳态染色质因子功能来阻止分化，产生可能具有治疗靶向的特异性染色质因子-转录因子相互作用。总之，我们的工作阐明了正常和恶性造血中染色质因子的谱系决定特性。批量离体和单细胞体内CRISPR敲除筛选用于表征小鼠造血过程中的680种染色质因子，突出了谱系特异性和正常和白血病特异性功能。
Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor–transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis. Bulk ex vivo and single-cell in vivo CRISPR knockout screens are used to characterize 680 chromatin factors during mouse hematopoiesis, highlighting lineage-specific and normal and leukemia-specific functions.
登录
查看更多内容
影响因子：
30.8
作者：
Douillet D;Sze CC;Ryan C;Piunti A;Shah AP;Ugarenko M;Marshall SA;Rendleman EJ;Zha D;Helmin KA;Zhao Z;Cao K;Morgan MA;Singer BD;Bartom ET;Smith ER;Shilatifard A
通讯作者：
Shilatifard A
DOI：
10.1073/pnas.0807297105
发表时间：
2008-09-30
影响因子：
11.1
作者：
Anderson, Ericka L.;Baltus, Andrew E.;Page, David C.
通讯作者：
Page, David C.
影响因子：
30.5
作者：
Cuartero S;Weiss FD;Dharmalingam G;Guo Y;Ing-Simmons E;Masella S;Robles-Rebollo I;Xiao X;Wang YF;Barozzi I;Djeghloul D;Amano MT;Niskanen H;Petretto E;Dowell RD;Tachibana K;Kaikkonen MU;Nasmyth KA;Lenhard B;Natoli G;Fisher AG;Merkenschlager M
通讯作者：
Merkenschlager M
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
30.8
作者：
Corces, M. Ryan;Buenrostro, Jason D.;Wu, Beijing;Greenside, Peyton G.;Chan, Steven M.;Koenig, Julie L.;Snyder, Michael P.;Pritchard, Jonathan K.;Kundaje, Anshul;Gkeenleaf, William J.;Majeti, Ravindra;Chang, Howard Y.
通讯作者：
Chang, Howard Y.