Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer.
The PAX3-FKHR fusion protein is present in a majority of alveolar rhabdomyosarcomas associated with increased aggressiveness and poor prognosis. To better understand the molecular pathogenesis of PAX3-FKHR, we carried out the first, unbiased genome-wide identification of PAX3-FKHR binding sites and associated target genes in alveolar rhabdomyosarcoma. The data shows that PAX3-FKHR binds to the same sites as PAX3 at both MYF5 and MYOD enhancers. The genome-wide analysis reveals that the PAX3-FKHR sites are (a) mostly distal to transcription start sites, (b) conserved, (c) enriched for PAX3 motifs, and (d) strongly associated with genes overexpressed in PAX3-FKHR-positive rhabdomyosarcoma cells and tumors. There is little evidence in our data set for PAX3-FKHR binding at the promoter sequences. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common coregulation for many target genes. We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma.
Cao
Liang
L
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Human Genome Research Institute, Bethesda, Maryland 20892, USA. caoli@mail.nih.gov
Yu
Yunkai
Y
Bilke
Sven
S
Walker
Robert L
RL
Mayeenuddin
Linnia H
LH
Azorsa
David O
DO
Yang
Fan
F
Pineda
Marbin
M
Helman
Lee J
LJ
Meltzer
Paul S
PS
D000077548:Anaplastic Lymphoma Kinase; D001665:Binding Sites; D045744:Cell Line, Tumor; D024721:E-Box Elements; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D050436:Regulatory Elements, Transcriptional; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism; D024363:Transcription Initiation Site; D015854:Up-Regulation
C459801:MYCN protein, human; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; C523321:PAX3-FKHR fusion protein, human; D000077548:Anaplastic Lymphoma Kinase; C496371:FGFR4 protein, human; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017526:Receptor, IGF Type 1