Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Cold Spring Harbor Laboratory Press
2014
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| Online Access: | http://hdl.handle.net/1721.1/85547 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1826196652315115520 |
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| author | Shi, Junwei Whyte, Warren A. Zepeda-Mendoza, Cinthya J. Milazzo, Joseph P. Shen, Chen Roe, Jae-Seok Minder, Jessica L. Mercan, Fatih Wang, Eric Eckersley-Maslin, Melanie A. Campbell, Amy E. Kawaoka, Shinpei Shareef, Sarah Zhu, Zhu Kendall, Jude Muhar, Matthias Haslinger, Christian Yu, Ming Roeder, Robert G. Wigler, Michael H. Blobel, Gerd A. Zuber, Johannes Spector, David L. Young, Richard A. Vakoc, Christopher R. |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Shi, Junwei Whyte, Warren A. Zepeda-Mendoza, Cinthya J. Milazzo, Joseph P. Shen, Chen Roe, Jae-Seok Minder, Jessica L. Mercan, Fatih Wang, Eric Eckersley-Maslin, Melanie A. Campbell, Amy E. Kawaoka, Shinpei Shareef, Sarah Zhu, Zhu Kendall, Jude Muhar, Matthias Haslinger, Christian Yu, Ming Roeder, Robert G. Wigler, Michael H. Blobel, Gerd A. Zuber, Johannes Spector, David L. Young, Richard A. Vakoc, Christopher R. |
| author_sort | Shi, Junwei |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:32:35Z |
| format | Article |
| id | mit-1721.1/85547 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:32:35Z |
| publishDate | 2014 |
| publisher | Cold Spring Harbor Laboratory Press |
| record_format | dspace |
| spelling | mit-1721.1/855472022-09-27T09:54:45Z Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation Shi, Junwei Whyte, Warren A. Zepeda-Mendoza, Cinthya J. Milazzo, Joseph P. Shen, Chen Roe, Jae-Seok Minder, Jessica L. Mercan, Fatih Wang, Eric Eckersley-Maslin, Melanie A. Campbell, Amy E. Kawaoka, Shinpei Shareef, Sarah Zhu, Zhu Kendall, Jude Muhar, Matthias Haslinger, Christian Yu, Ming Roeder, Robert G. Wigler, Michael H. Blobel, Gerd A. Zuber, Johannes Spector, David L. Young, Richard A. Vakoc, Christopher R. Whitehead Institute for Biomedical Research Whyte, Warren A. Young, Richard A. 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. Starr Cancer Consortium (grant I5-A539) Starr Cancer Consortium (grant I4-A430) Edward P. Evans Foundation SASS Foundation for Medical Research, Inc F. M. Kirby Foundation Alex's Lemonade Stand Foundation Lauri Strauss Leukemia Foundation V Foundation for Cancer Research Burroughs Wellcome Fund (Career Award) National Institutes of Health (U.S.) (grant NCI RO1 CA174793) Cold Spring Harbor Laboratory (National Cancer Institute Cancer Center Support grant CA45508) National Institute of General Medical Sciences (U.S.) ((NIGMS) 42694) National Cancer Institute (U.S.) (5P01CA013106) National Cancer Institute (U.S.) (R37DK058044) National Cancer Institute (U.S.) (R01 HG002668) Leukemia & Lymphoma Society of America (Specialized Center of Research (SCOR) grant 7132-08) 2014-03-06T20:21:39Z 2014-03-06T20:21:39Z 2013-11 2013-11 Article http://purl.org/eprint/type/JournalArticle 0890-9369 http://hdl.handle.net/1721.1/85547 Shi, J., W. A. Whyte, C. J. Zepeda-Mendoza, J. P. Milazzo, C. Shen, J.-S. Roe, J. L. Minder, et al. “Role of SWI/SNF in Acute Leukemia Maintenance and Enhancer-Mediated Myc Regulation.” Genes & Development 27, no. 24 (December 15, 2013): 2648–2662. https://orcid.org/0000-0001-8855-8647 en_US http://dx.doi.org/10.1101/gad.232710.113 Genes & Development Creative Commons Attribution-Non-Commercial 3.0 (CC-BY-NC) http://creativecommons.org/licenses/by-nc/3.0/ application/pdf Cold Spring Harbor Laboratory Press Genes and Development |
| spellingShingle | Shi, Junwei Whyte, Warren A. Zepeda-Mendoza, Cinthya J. Milazzo, Joseph P. Shen, Chen Roe, Jae-Seok Minder, Jessica L. Mercan, Fatih Wang, Eric Eckersley-Maslin, Melanie A. Campbell, Amy E. Kawaoka, Shinpei Shareef, Sarah Zhu, Zhu Kendall, Jude Muhar, Matthias Haslinger, Christian Yu, Ming Roeder, Robert G. Wigler, Michael H. Blobel, Gerd A. Zuber, Johannes Spector, David L. Young, Richard A. Vakoc, Christopher R. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation |
| title | Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation |
| title_full | Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation |
| title_fullStr | Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation |
| title_full_unstemmed | Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation |
| title_short | Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation |
| title_sort | role of swi snf in acute leukemia maintenance and enhancer mediated myc regulation |
| url | http://hdl.handle.net/1721.1/85547 https://orcid.org/0000-0001-8855-8647 |
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