MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.
MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.
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DOI：
10.1038/s41467-023-40981-9
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发表时间：
2023-08-25
影响因子：
16.6
通讯作者：
Milne, Thomas A.
中科院分区：
文献类型：
--
作者：
Crump, Nicholas T.;Smith, Alastair L.;Godfrey, Laura;Dopico-Fernandez, Ana M.;Denny, Nicholas;Harman, Joe R.;Hamley, Joseph C.;Jackson, Nicole E.;Chahrour, Catherine;Riva, Simone;Rice, Siobhan;Kim, Jaehoon;Basrur, Venkatesha;Fermin, Damian;Elenitoba-Johnson, Kojo;Roeder, Robert G.;Allis, C. David;Roberts, Irene;Roy, Anindita;Geng, Huimin;Davies, James O. J.;Milne, Thomas A.
在许多癌症中，异常的增强子激活是驱动癌基因表达的关键机制。虽然人们对真核生物中较大的染色体结构域的调控知之甚少，但增强子-启动子相互作用的细节仍然知之甚少。最近的工作表明，像BRD4和Mediator这样的共激活因子对增强子-启动子相互作用的影响很小。在由MLL-AF4融合蛋白控制的白血病中，我们使用超高分辨率技术Micro-Capture-C(MCC)来表明MLL-AF4结合促进了关键靶点子集上广泛的、高密度的增强子-启动子相互作用区域。这些增强子富含PAF1C和FACT等转录延伸因子，这些因子的缺失会取消增强子-启动子的接触。这项工作不仅为MLL-AF4如何能够驱动白血病关键基因的高水平转录提供了一个额外的模型，而且还提出了一个更一般的模型，将增强子-启动子串扰和转录延伸联系起来。以前的研究已经报道了MLL-AF4与基因内和基因间的增强子结合，然而，MLL-AF4在增强子功能中的作用仍有待研究。在这里，作者表明MLL-AF4与PAF1和FAT在增强子上合作，以促进白血病中与癌基因启动子的高密度相互作用。
Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation. Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.
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影响因子：
3.4
作者：
Deutsch, Eric W.;Mendoza, Luis;Shteynberg, David;Farrah, Terry;Lam, Henry;Tasman, Natalie;Sun, Zhi;Nilsson, Erik;Pratt, Brian;Prazen, Bryan;Eng, Jimmy K.;Martin, Daniel B.;Nesvizhskii, Alexey I.;Aebersold, Ruedi
通讯作者：
Aebersold, Ruedi
影响因子：
64.5
作者：
Bai X;Kim J;Yang Z;Jurynec MJ;Akie TE;Lee J;LeBlanc J;Sessa A;Jiang H;DiBiase A;Zhou Y;Grunwald DJ;Lin S;Cantor AB;Orkin SH;Zon LI
通讯作者：
Zon LI
婴儿MLL重新培养急性淋巴细胞白血病中体细胞突变的景观。
影响因子：
30.8
作者：
Andersson AK;Ma J;Wang J;Chen X;Gedman AL;Dang J;Nakitandwe J;Holmfeldt L;Parker M;Easton J;Huether R;Kriwacki R;Rusch M;Wu G;Li Y;Mulder H;Raimondi S;Pounds S;Kang G;Shi L;Becksfort J;Gupta P;Payne-Turner D;Vadodaria B;Boggs K;Yergeau D;Manne J;Song G;Edmonson M;Nagahawatte P;Wei L;Cheng C;Pei D;Sutton R;Venn NC;Chetcuti A;Rush A;Catchpoole D;Heldrup J;Fioretos T;Lu C;Ding L;Pui CH;Shurtleff S;Mullighan CG;Mardis ER;Wilson RK;Gruber TA;Zhang J;Downing JR;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
通讯作者：
St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
影响因子：
30.8
作者：
Armstrong, SA;Staunton, JE;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
16.6
作者：
Crump NT;Ballabio E;Godfrey L;Thorne R;Repapi E;Kerry J;Tapia M;Hua P;Lagerholm C;Filippakopoulos P;Davies JOJ;Milne TA
通讯作者：
Milne TA