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. (November 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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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:	Eckersley-Maslin, Melanie A. Kawaoka, Shinpei Kendall, Jude T. Mercan, Fatih Milazzo, Joseph Minder, Jessica Roe, Jae Seok Shareef, Sarah Shen, Chen Shi, Junwei Spector, David L. Vakoc, Christopher R. Wang, Eric Wigler, Michael H. Zepeda Mendoza, Cinthya Zhu, Zhu
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 School of Biological Sciences > Publications CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User:	Matt Covey
Date:	27 November 2013
Date Deposited:	09 Dec 2013 17:38
Last Modified:	05 Nov 2015 15:36
PMCID:	PMC3877755
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/28899

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