Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation.
Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation.
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DOI：
10.1101/gad.232710.113
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发表时间：
2013-12-15
影响因子：
10.5
通讯作者：
Vakoc CR
中科院分区：
文献类型：
--
作者：
Shi J;Whyte WA;Zepeda-Mendoza CJ;Milazzo JP;Shen C;Roe JS;Minder JL;Mercan F;Wang E;Eckersley-Maslin MA;Campbell AE;Kawaoka S;Shareef S;Zhu Z;Kendall J;Muhar M;Haslinger C;Yu M;Roeder RG;Wigler MH;Blobel GA;Zuber J;Spector DL;Young RA;Vakoc CR
癌细胞经常依赖染色质调节剂来维持其恶性表型。BRG1是SWI/SNF的ATPase亚单位，已知在几种细胞类型中抑制肿瘤形成。Vakoc和他的同事现在表明，白血病细胞转而依赖BRG1来支持他们的致癌转录计划，其中包括Myc作为关键靶点。BRG1对于维持转录因子的占位和实现与Myc启动子的长距离环相互作用至关重要。因此，这些发现暗示了增强子介导的Myc调控在白血病发病机制中的作用。癌细胞经常依赖染色质调节活性来维持恶性表型。在这里，我们表明，白血病细胞需要哺乳动物的SWI/SNF染色质重塑复合体才能生存和异常的自我更新能力。虽然已知SWI/SNF的ATPase亚单位BRG1在几种细胞类型中抑制肿瘤形成，但我们发现白血病细胞转而依赖BRG1来支持其致癌转录程序，其中包括Myc作为其关键靶点之一。为了解释这种上下文特定的功能，我们确定了位于Myc下游1.7Mb的一组谱系特异性增强子，它们被SWI/SNF和BET蛋白Brd4占据。这些远端元件需要BRG1来维持转录因子的占位，以及与Myc启动子的长距离染色质环相互作用。值得注意的是，这些远端Myc增强子与∼3%的急性髓系白血病中局部扩增的区域一致。总之，这些发现定义了SWI/SNF的白血病维持功能，该功能与增强子介导的基因调控有关，为癌细胞如何利用转录辅助激活因子维持致癌基因表达程序提供了一般性的见解。
Cancer cells frequently depend on chromatin regulators to maintain their malignant phenotype. Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cell types. Vakoc and colleagues now show that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as a key target. Brg1 is critical to sustain transcription factor occupancy and enable long-range looping interactions with the Myc promoter. These findings thus implicate enhancer-mediated Myc regulation in leukemia pathogenesis. Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cell types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc that are occupied by SWI/SNF as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in ∼3% of acute myeloid leukemias. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs.
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哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
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影响因子：
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--
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS
影响因子：
20.3
作者：
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通讯作者：
Sauvageau, Guy
影响因子：
10.5
作者：
Bultman, SJ;Gebuhr, TC;Magnuson, T
通讯作者：
Magnuson, T