title: Chromatin accessibility, p300, and histone acetylation define PML-RARα and AML1-ETO binding sites in acute myeloid leukemia.
abstract: Chromatin accessibility plays a key role in regulating cell type specific gene expression during hematopoiesis but has also been suggested to be aberrantly regulated during leukemogenesis. To understand the leukemogenic chromatin signature, we analyzed acute promyelocytic leukemia, a subtype of leukemia characterized by the expression of RARα-fusion proteins, such as PML-RARα. We used nuclease accessibility sequencing in cell lines as well as patient blasts to identify accessible DNA elements and identified > 100 000 accessible regions in each case. Using ChIP-seq, we identified H2A.Z as a histone modification generally associated with these accessible regions, whereas unsupervised clustering analysis of other chromatin features, including DNA methylation, H2A.Zac, H3ac, H3K9me3, H3K27me3, and the regulatory factor p300, distinguished 6 distinct clusters of accessible sites, each with a characteristic functional makeup. Of these, PML-RARα binding was found specifically at accessible chromatin regions characterized by p300 binding and hypoacetylated histones. Identifying regions with a similar epigenetic make up in t(8;21) acute myeloid leukemia (AML) cells, another subtype of AMLs, revealed that these regions are occupied by the oncofusion protein AML1-ETO. Together, our results suggest that oncofusion proteins localize to accessible regions and that chromatin accessibility together with p300 binding and histone acetylation characterize AML1-ETO and PML-RARα binding sites.
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Sadia
authors.initials: S
authors.lastname: Saeed
authors.forename: Colin
authors.initials: C
authors.lastname: Logie
authors.forename: Kees-Jan
authors.initials: KJ
authors.lastname: Francoijs
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Frigè
authors.forename: Mauro
authors.initials: M
authors.lastname: Romanenghi
authors.forename: Fiona G
authors.initials: FG
authors.lastname: Nielsen
authors.forename: Lianne
authors.initials: L
authors.lastname: Raats
authors.forename: Maryam
authors.initials: M
authors.lastname: Shahhoseini
authors.forename: Martijn
authors.initials: M
authors.lastname: Huynen
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Martens
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C107844:AML1-ETO fusion protein, human; D014408:Biomarkers, Tumor; D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human