title: Hemgn is a direct transcriptional target of HOXB4 and induces expansion of murine myeloid progenitor cells.
abstract: HOXB4, a member of the Homeobox transcription factor family, promotes expansion of hematopoietic stem cells and hematopoietic progenitor cells in vivo and ex vivo when overexpressed. However, the molecular mechanisms underlying this effect are not well understood. To identify direct target genes of HOXB4 in primary murine hematopoietic progenitor cells, we induced HOXB4 function in lineage-negative murine bone marrow cells, using a tamoxifen-inducible HOXB4-ER(T2) fusion protein. Using expression microarrays, 77 probe sets were identified with differentially changed expression in early response to HOXB4 induction. Among them, we show that Hemogen (Hemgn), encoding a hematopoietic-specific nuclear protein of unknown function, is a direct transcriptional target of HOXB4. We show that HOXB4 binds to the promoter region of Hemgn both ex vivo and in vivo. When we overexpressed Hemgn in bone marrow cells, we observed that Hemgn promoted cellular expansion in liquid cultures and increased self-renewal of myeloid colony-forming units in culture, partially recapitulating the effect of HOXB4 overexpression. Furthermore, down-regulation of Hemgn using an shRNA strategy proved that Hemgn contributes to HOXB4-mediated expansion in our myeloid progenitor assays. Our results identify a functionally relevant, direct transcriptional target of HOXB4 and identify other target genes that may also participate in the HOXB4 genetic network.
authors.affiliation: Experimental Hematology Division, Department of Hematology, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shou
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhou
authors.forename: Taihe
authors.initials: T
authors.lastname: Lu
authors.forename: Brian P
authors.initials: BP
authors.lastname: Sorrentino
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division; D047369:Chromatin Immunoprecipitation; D003114:Colony-Forming Units Assay; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects*; D038042:Myelopoiesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C090460:HOXB4 protein, human; C486660:Hemgn protein, mouse; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors
references.citation: Blood. 2004 Oct 15;104(8):2307-14
references.pmid: 15226173
references.citation: Mol Cell Biol. 1994 Jul;14(7):4532-45
references.pmid: 7911971
references.citation: Blood. 2004 Jun 1;103(11):4126-33
references.pmid: 14962901
references.citation: Oncogene. 2007 Oct 15;26(47):6766-76
references.pmid: 17934484
references.citation: Cell. 2002 Apr 5;109(1):39-45
references.pmid: 11955445
references.citation: Cell. 2008 Feb 22;132(4):631-44
references.pmid: 18295580
references.citation: Genesis. 2000 Sep;28(1):15-22
references.pmid: 11020712
references.citation: Leukemia. 2007 Nov;21(11):2277-86
references.pmid: 17690693
references.citation: Genes Dev. 1994 Mar 15;8(6):732-44
references.pmid: 7926763
references.citation: Genes Dev. 1995 Jul 15;9(14):1753-65
references.pmid: 7622039
references.citation: Cell. 2002 Apr 5;109(1):29-37
references.pmid: 11955444
references.citation: Leukemia. 2005 Aug;19(8):1499-502
references.pmid: 15920494
references.citation: Nat Rev Immunol. 2004 Nov;4(11):878-88
references.pmid: 15516967
references.citation: Leukemia. 2005 Jan;19(1):148-53
references.pmid: 15496973
references.citation: Blood. 2003 Mar 1;101(5):1759-68
references.pmid: 12406897
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12101-6
references.pmid: 16093308
references.citation: J Exp Med. 2000 Jan 17;191(2):253-64
references.pmid: 10637270
references.citation: Nucleic Acids Res. 1999 Nov 15;27(22):4324-7
references.pmid: 10536138
references.citation: Dev Dyn. 2003 Dec;228(4):606-16
references.pmid: 14648837
references.citation: Annu Rev Immunol. 2003;21:759-806
references.pmid: 12615892
references.citation: Stem Cells Dev. 2009 Jun;18(5):783-92
references.pmid: 18808325
references.citation: Blood. 1997 Sep 1;90(5):1777-86
references.pmid: 9292510
references.citation: Nature. 2008 May 15;453(7193):306-13
references.pmid: 18480811
references.citation: Heredity (Edinb). 2006 Aug;97(2):88-96
references.pmid: 16721389
references.citation: Immunity. 2003 Apr;18(4):561-71
references.pmid: 12705858
references.citation: Mech Dev. 2001 Jun;104(1-2):105-11
references.pmid: 11404085
references.citation: Mol Ther. 2002 Mar;5(3):242-51
references.pmid: 11863413
references.citation: Exp Hematol. 2000 May;28(5):569-74
references.pmid: 10812247
references.citation: Blood. 2009 May 21;113(21):5111-20
references.pmid: 19270262
references.citation: Science. 2005 Feb 18;307(5712):1101-4
references.pmid: 15718471
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16952-7
references.pmid: 17940039
references.citation: J Exp Med. 2000 Dec 18;192(12):1707-18
references.pmid: 11120768
references.citation: Cell Death Differ. 2004 Dec;11(12):1299-308
references.pmid: 15332117