PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia.
PML/RARalpha is of crucial importance in acute promyelocytic leukemia (APL) both pathologically and therapeutically. Using a genome-wide approach, we identified in vivo PML/RARalpha binding sites in a PML/RARalpha-inducible cell model. Of the 2979 targeted regions, >62% contained canonical PU.1 motifs and >84% of these PU.1 motifs coexisted with one or more RARE half (RAREh) sites in nearby regions. Promoters with such PU.1-RAREh binding sites were transactivated by PU.1. PU.1-mediated transactivation was repressed by PML/RARalpha and restored by the addition of all-trans retinoic acid (ATRA). Genes containing such promoters were significantly represented by genes transcriptionally suppressed in APL and/or reactivated upon treatment with ATRA. Thus, selective targeting of PU.1-regulated genes by PML/RARalpha is a critical mechanism for the pathogenesis of APL.
Wang
Kankan
K
Sino-French Research Center for Life Sciences and Genomics, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, China.
Wang
Ping
P
Shi
Jiantao
J
Zhu
Xuehua
X
He
Miaomiao
M
Jia
Xiaohong
X
Yang
Xianwen
X
Qiu
Fei
F
Jin
Wen
W
Qian
Maoxiang
M
Fang
Hai
H
Mi
Jianqing
J
Yang
Xuzhi
X
Xiao
Huasheng
H
Minden
Mark
M
Du
Yanzhi
Y
Chen
Zhu
Z
Zhang
Ji
J
D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D016384:Consensus Sequence; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein