title: Genome-wide analysis of target genes regulated by HoxB4 in hematopoietic stem and progenitor cells developing from embryonic stem cells.
abstract: Forced expression of the transcription factor HoxB4 has been shown to enhance the self-renewal capacity of mouse bone marrow hematopoietic stem cells (HSCs) and confer a long-term repopulating capacity to yolk sac and embryonic stem (ES) cell-derived hematopoietic precursors. The fact that ES cell-derived precursors do not repopulate bone marrow without HoxB4 underscores an important role for HoxB4 in the maturation of ES-derived hematopoietic precursors into long-term repopulating HSCs. However, the precise molecular mechanism underlying this process is barely understood. In this study, we performed a genome-wide analysis of HoxB4 using ES cell-derived hematopoietic stem/progenitor cells. The results revealed many of the genes essential for HSC development to be direct targets of HoxB4, such as Runx1, Scl/Tal1, Gata2, and Gfi1. The expression profiling also showed that HoxB4 indirectly affects the expression of several important genes, such as Lmo2, Erg, Meis1, Pbx1, Nov, AhR, and Hemgn. HoxB4 tended to activate the transcription, but the down-regulation of a significant portion of direct targets suggested its function to be context-dependent. These findings indicate that HoxB4 reprograms a set of key regulator genes to facilitate the maturation of developing HSCs into repopulating cells. Our list of HoxB4 targets also provides novel candidate regulators for HSCs.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Oshima
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Endoh
authors.forename: Takaho A
authors.initials: TA
authors.lastname: Endo
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Toyoda
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Nakajima-Takagi
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sugiyama
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.forename: Mitsujiro
authors.initials: M
authors.lastname: Osawa
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D030541:Databases, Genetic; D053595:Embryonic Stem Cells / Q000502:physiology*; D050989:GATA2 Transcription Factor / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D055106:Genome-Wide Association Study; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C494712:Gata2 protein, mouse; C079873:Gfi1 protein, mouse; C513262:Hoxb4 protein, mouse; C493726:Runx1 protein, mouse; C489366:Tal1 protein, mouse