title: Identification and characterization of Hoxa9 binding sites in hematopoietic cells.
abstract: The clustered homeobox proteins play crucial roles in development, hematopoiesis, and leukemia, yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 cobind at hundreds of highly evolutionarily conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation, and transcriptional activation of a network of proto-oncogenes, including Erg, Flt3, Lmo2, Myb, and Sox4. Collectively, this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, 48109-0602, USA.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Huang
authors.forename: Kajal
authors.initials: K
authors.lastname: Sitwala
authors.forename: Joel
authors.initials: J
authors.lastname: Bronstein
authors.forename: Daniel
authors.initials: D
authors.lastname: Sanders
authors.forename: Monisha
authors.initials: M
authors.lastname: Dandekar
authors.forename: Cailin
authors.initials: C
authors.lastname: Collins
authors.forename: Gordon
authors.initials: G
authors.lastname: Robertson
authors.forename: James
authors.initials: J
authors.lastname: MacDonald
authors.forename: Timothee
authors.initials: T
authors.lastname: Cezard
authors.forename: Misha
authors.initials: M
authors.lastname: Bilenky
authors.forename: Nina
authors.initials: N
authors.lastname: Thiessen
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Thomas
authors.initials: T
authors.lastname: Zeng
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Alfred
authors.initials: A
authors.lastname: Hero
authors.forename: Steven
authors.initials: S
authors.lastname: Jones
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic; D057890:Epigenomics; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C097899:homeobox protein HOXA9
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