TY - JOUR
T1 - Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation
AU - Shi, Junwei
AU - Whyte, Warren A.
AU - Zepeda-Mendoza, Cinthya J.
AU - Milazzo, Joseph P.
AU - Shen, Chen
AU - Roe, Jae Seok
AU - Minder, Jessica L.
AU - Mercan, Fatih
AU - Wang, Eric
AU - Eckersley-Maslin, Melanie A.
AU - Campbell, Amy E.
AU - Kawaoka, Shinpei
AU - Shareef, Sarah
AU - Zhu, Zhu
AU - Kendall, Jude
AU - Muhar, Matthias
AU - Haslinger, Christian
AU - Yu, Ming
AU - Roeder, Robert G.
AU - Wigler, Michael H.
AU - Blobel, Gerd A.
AU - Zuber, Johannes
AU - Spector, David L.
AU - Young, Richard A.
AU - Vakoc, Christopher R.
PY - 2013/12/15
Y1 - 2013/12/15
N2 - 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.
AB - 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.
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U2 - 10.1101/gad.232710.113
DO - 10.1101/gad.232710.113
M3 - Article
C2 - 24285714
AN - SCOPUS:84890717859
SN - 0890-9369
VL - 27
SP - 2648
EP - 2662
JO - Genes and Development
JF - Genes and Development
IS - 24
ER -
