Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation [ChIP-Seq]

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 cancer 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 megabases downstream of 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 leukemia. 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 Overall design: In order to understanding the lineage specific requirement of coactivaor, such as Brg1 and Brd4, in AML, we performed ChIP-seq with Brg1, Brd4 together with histone modification marks in murine MLL-AF9/NrasG12D AML cell line to search tissue specific cis regulation element that can be accounted for the leukemia specific dependence.

癌细胞通常依赖染色质调控活性以维持恶性表型。本研究表明，白血病细胞的存活与异常自我更新潜能依赖于哺乳动物SWI/SNF染色质重塑复合物。尽管已知SWI/SNF的ATP酶亚基Brg1在多种癌症类型中可抑制肿瘤发生，但本研究发现白血病细胞反而依赖Brg1来维持其致癌转录程序，而Myc正是该程序的关键靶标之一。为阐释这一情境特异性功能，我们鉴定出一簇位于Myc基因下游1.7兆碱基处的谱系特异性增强子，该区域可被SWI/SNF以及BET蛋白Brd4结合。在这些远端调控元件处，Brg1对于维持转录因子占据状态以及介导与Myc启动子的远程染色质环互作至关重要。值得注意的是，这些Myc远端增强子所在区域与3%急性髓系白血病（AML）中发生局灶扩增的区域重合。综上，本研究明确了SWI/SNF的白血病维持功能与增强子介导的基因调控相关，为解析癌细胞如何利用转录共激活因子维持致癌基因表达程序提供了通用视角。整体实验设计：为阐明共激活因子（如Brg1与Brd4）在急性髓系白血病（AML）中的谱系特异性需求，我们对小鼠MLL-AF9/NrasG12D AML细胞系中的Brg1、Brd4以及组蛋白修饰标记进行了染色质免疫共沉淀测序（ChIP-seq），以筛选可解释白血病特异性依赖现象的组织特异性顺式调控元件。