Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation.
نویسندگان
چکیده
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.
منابع مشابه
A role for the yeast SWI/SNF complex in DNA replication.
The yeast SWI/SNF complex is required for expression of many genes and for the full functioning of several transcriptional activators. Genetic and biochemical studies indicate that SWI/SNF uses the energy of ATP hydrolysis to antagonize chromatin-mediated transcriptional repression. We have tested the possibility that SWI/SNF might also play a role in DNA replication. A mitotic minichromosome s...
متن کاملThe c-myc gene is a direct target of mammalian SWI/SNF-related complexes during differentiation-associated cell cycle arrest.
The activity of mammalian SWI/SNF-related chromatin remodeling complexes is crucial for differentiation, development, and tumor suppression. Cell cycle-regulating activities dependent on the complexes include induction of the p21(WAF1/CIP1) kinase inhibitor and repression of E2F-responsive promoters. These responses are linked through effects on pRb phosphorylation, but the direct role of the S...
متن کاملThe SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers
Genes encoding subunits of SWI/SNF (BAF) chromatin remodelling complexes are collectively altered in over 20% of human malignancies, but the mechanisms by which these complexes alter chromatin to modulate transcription and cell fate are poorly understood. Utilizing mouse embryonic fibroblast and cancer cell line models, here we show via ChIP-seq and biochemical assays that SWI/SNF complexes are...
متن کاملSWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance
Alterations in chromatin structure caused by deregulated epigenetic mechanisms collaborate with underlying genetic lesions to promote cancer. SMARCA4/BRG1, a core component of the SWI/SNF ATP-dependent chromatin-remodelling complex, has been implicated by its mutational spectrum as exerting a tumour-suppressor function in many solid tumours; recently however, it has been reported to sustain leu...
متن کاملMYC interaction with the tumor suppressive SWI/SNF complex member INI1 regulates transcription and cellular transformation
MYC is a key driver of cellular transformation and is deregulated in most human cancers. Studies of MYC and its interactors have provided mechanistic insight into its role as a regulator of gene transcription. MYC has been previously linked to chromatin regulation through its interaction with INI1 (SMARCB1/hSNF5/BAF47), a core member of the SWI/SNF chromatin remodeling complex. INI1 is a potent...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Genes & development
دوره 27 24 شماره
صفحات -
تاریخ انتشار 2013