Chromatin modifications induced by PML-RARalpha repress critical targets in leukemogenesis as analyzed by ChIP-Chip.
The translocation t(15;17) generates the chimeric PML-RARalpha transcription factor that is the initiating event of acute promyelocytic leukemia. A global view of PML-RARalpha transcriptional functions was obtained by genome-wide binding and chromatin modification analyses combined with genome-wide expression data. Chromatin immunoprecipitation (ChIP)-chip experiments identified 372 direct genomic PML-RARalpha targets. A subset of these was confirmed in primary acute promyelocytic leukemia. Direct PML-RARalpha targets include regulators of global transcriptional programs as well as critical regulatory genes for basic cellular functions such as cell-cycle control and apoptosis. PML-RARalpha binding universally led to HDAC1 recruitment, loss of histone H3 acetylation, increased tri-methylation of histone H3 lysine 9, and unexpectedly increased trimethylation of histone H3 lysine 4. The binding of PML-RARalpha to target promoters and the resulting histone modifications resulted in mRNA repression of functionally relevant genes. Taken together, our results reveal that the transcription factor PML-RARalpha regulates key cancer-related genes and pathways by inducing a repressed chromatin formation on its direct genomic target genes.
Hoemme
Claudia
C
Department of Medicine, Hematology and Oncology and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, Domagkstrasse 3, Münster, Germany.
Peerzada
Abdul
A
Behre
Gerhard
G
Wang
Yipeng
Y
McClelland
Michael
M
Nieselt
Kay
K
Zschunke
Matthias
M
Disselhoff
Christine
C
Agrawal
Shuchi
S
Isken
Fabienne
F
Tidow
Nicola
N
Berdel
Wolfgang E
WE
Serve
Hubert
H
Müller-Tidow
Carsten
C
D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015894:Genome, Human / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020298:U937 Cells
D002843:Chromatin; D006657:Histones; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein