title: Chromatin modifications induced by PML-RARalpha repress critical targets in leukemogenesis as analyzed by ChIP-Chip.
abstract: 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.
authors.affiliation: Department of Medicine, Hematology and Oncology and Interdisciplinary Center for Clinical Research (IZKF), University of Münster, Domagkstrasse 3, Münster, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hoemme
authors.forename: Abdul
authors.initials: A
authors.lastname: Peerzada
authors.forename: Gerhard
authors.initials: G
authors.lastname: Behre
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: McClelland
authors.forename: Kay
authors.initials: K
authors.lastname: Nieselt
authors.forename: Matthias
authors.initials: M
authors.lastname: Zschunke
authors.forename: Christine
authors.initials: C
authors.lastname: Disselhoff
authors.forename: Shuchi
authors.initials: S
authors.lastname: Agrawal
authors.forename: Fabienne
authors.initials: F
authors.lastname: Isken
authors.forename: Nicola
authors.initials: N
authors.lastname: Tidow
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
mesh_terms: 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
chemical_list: D002843:Chromatin; D006657:Histones; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein