Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation

Shi, J., Whyte, W. A., Zepeda-Mendoza, C. J., Milazzo, J. P., Shen, C., Roe, J. S., Minder, J. L., Mercan, F., Wang, E., Eckersley-Maslin, M. A., Campbell, A. E., Kawaoka, S., Shareef, S., Zhu, Z., Kendall, J., Muhar, M., Haslinger, C., Yu, M., Roeder, R. G., Wigler, M. A., Blobel, G. A., Zuber, J., Spector, D. L., Young, R. A., Vakoc, C. R. (2013) Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes and Development, 27 (24). pp. 264-273. ISSN 08909369 (ISSN)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/24285714
DOI: 10.1101/gad.232710.113

Abstract

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 approximately 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.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Chromatin dynamics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Genetic Screening Service
CSHL Cancer Center Shared Resources > Instrumentation Service
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL Cancer Center Shared Resources > Next Generation Sequencing Service
CSHL labs > Spector lab
CSHL labs > Vakoc lab
CSHL labs > Wigler lab
Watson School > Publications
CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User: Matt Covey
Date Deposited: 09 Dec 2013 17:38
Last Modified: 05 Nov 2015 15:36
PMCID: PMC3877755
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28899

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