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PMID: 18474618 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

MicroRNA-126 regulates HOXA9 by binding to the homeobox.

Molecular and cellular biology ·Vol. 28 ·No. 14 ·2008-07-00 ·Pages 4609-19

Shen WF, Hu YL, Uttarwar L, Passegue E, Largman C

Abstract

The PicTar program predicted that microRNA-126 (miR-126), miR-145, and let-7s target highly conserved sites within the Hoxa9 homeobox. There are increased nucleotide constraints in the three microRNA seed sites among Hoxa9 genes beyond that required to maintain protein identity, suggesting additional functional conservation. In preliminary experiments, forced expression of these microRNAs in Hoxa9-immortalized bone marrow cells downregulated the HOXA9 protein and caused loss of biological activity. The microRNAs were shown to target their predicted sites within the homeobox. miR-126 and Hoxa9 mRNA are coexpressed in hematopoietic stem cells and downregulated in parallel during progenitor cell differentiation; however, miR-145 is barely detectable in hematopoietic cells, and let-7s are highly expressed in bone marrow progenitors, suggesting that miR-126 may function in normal hematopoietic cells to modulate HOXA9 protein. In support of this hypothesis, expression of miR-126 alone in MLL-ENL-immortalized bone marrow cells decreased endogenous HOXA9 protein, while inhibition of endogenous miR-126 increased expression of HOXA9 in F9 cells.

MeSH Terms
Amino Acid Sequence Animals Base Sequence Bone Marrow Cells/metabolism Cell Line, Tumor Conserved Sequence Down-Regulation Genes, Homeobox Homeodomain Proteins/genetics,metabolism Humans Leukemia, Promyelocytic, Acute/genetics,metabolism Mice MicroRNAs/metabolism Molecular Sequence Data Sequence Alignment
Chemicals
Homeodomain Proteins MIRN126 microRNA, human MicroRNAs homeobox protein HOXA9
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Shen Wei-Fang
Department of Medicine, University of California, San Francisco, California, USA. wfshen@itsa.ucsf.edu
Hu Yu-Long
Uttarwar Lalita
Passegue Emmanuelle
Largman Corey
References (49)
49 references, click to expand
  1. Loss of function of the homeobox gene Hoxa-9 perturbs early T-cell development and induces apoptosis in primitive thymocytes.
    Blood. 1998 Jul 15;92(2):383-93 PMID: 9657735
  2. MicroRNA targeting specificity in mammals: determinants beyond seed pairing.
    Mol Cell. 2007 Jul 6;27(1):91-105 PMID: 17612493
  3. RegRNA: an integrated web server for identifying regulatory RNA motifs and elements.
    Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W429-34 PMID: 16845041
  4. Targeted mutations in hoxa-9 and hoxb-9 reveal synergistic interactions.
    Dev Biol. 1997 Jan 15;181(2):186-96 PMID: 9013929
  5. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex.
    Mol Cell. 2004 Jul 2;15(1):57-67 PMID: 15225548
  6. Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells.
    J Exp Med. 2005 Jun 6;201(11):1825-35 PMID: 15928198
  7. Hox genes in vertebrate development.
    Cell. 1994 Jul 29;78(2):191-201 PMID: 7913880
  8. New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors.
    Cell. 2006 Jul 28;126(2):415-26 PMID: 16873070
  9. Human Hox-4.2 and Drosophila deformed encode similar regulatory specificities in Drosophila embryos and larvae.
    Cell. 1990 Nov 30;63(5):969-76 PMID: 1979526
  10. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes.
    Biol Reprod. 1997 Dec;57(6):1338-45 PMID: 9408238
  11. Plant and animal microRNAs: similarities and differences.
    Funct Integr Genomics. 2005 Jul;5(3):129-35 PMID: 15875226
  12. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis.
    Blood. 1997 Mar 15;89(6):1922-30 PMID: 9058712
  13. hDOT1L links histone methylation to leukemogenesis.
    Cell. 2005 Apr 22;121(2):167-78 PMID: 15851025
  14. The Abd-B-like Hox homeodomain proteins can be subdivided by the ability to form complexes with Pbx1a on a novel DNA target.
    J Biol Chem. 1997 Mar 28;272(13):8198-206 PMID: 9079637
  15. Changes in HOXB6 homeodomain protein structure and localization during human epidermal development and differentiation.
    Dev Dyn. 2000 Aug;218(4):636-47 PMID: 10906782
  16. Combinatorial microRNA target predictions.
    Nat Genet. 2005 May;37(5):495-500 PMID: 15806104
  17. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b.
    EMBO J. 1998 Jul 1;17(13):3714-25 PMID: 9649441
  18. Human MicroRNA targets.
    PLoS Biol. 2004 Nov;2(11):e363 PMID: 15502875
  19. MicroInspector: a web tool for detection of miRNA binding sites in an RNA sequence.
    Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W696-700 PMID: 15980566
  20. "Mir"acles in hox gene regulation.
    Bioessays. 2006 May;28(5):445-8 PMID: 16615131
  21. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization.
    Mol Cell Biol. 2004 Jan;24(2):617-28 PMID: 14701735
  22. A combined computational-experimental approach predicts human microRNA targets.
    Genes Dev. 2004 May 15;18(10):1165-78 PMID: 15131085
  23. Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias.
    Leukemia. 1999 Dec;13(12):1993-9 PMID: 10602420
  24. Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins.
    Genes Dev. 1995 Mar 15;9(6):663-74 PMID: 7729685
  25. Homeodomain-DNA recognition.
    Cell. 1994 Jul 29;78(2):211-23 PMID: 8044836
  26. Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning.
    Development. 1996 Feb;122(2):461-72 PMID: 8625797
  27. Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent promyelocyte capable of biphenotypic differentiation to neutrophils or macrophages, independent of enforced meis expression.
    Mol Cell Biol. 2000 May;20(9):3274-85 PMID: 10757811
  28. CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes.
    Leukemia. 2005 Nov;19(11):1948-57 PMID: 16107895
  29. Protein kinase C-mediated phosphorylation of the leukemia-associated HOXA9 protein impairs its DNA binding ability and induces myeloid differentiation.
    Mol Cell Biol. 2004 May;24(9):3827-37 PMID: 15082777
  30. Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in chronic phase.
    Leukemia. 2007 Mar;21(3):494-504 PMID: 17252012
  31. A conserved non-homeodomain Hoxa9 isoform interacting with CBP is co-expressed with the 'typical' Hoxa9 protein during embryogenesis.
    Gene Expr Patterns. 2004 Mar;4(2):215-22 PMID: 15161102
  32. Substrate requirements for let-7 function in the developing zebrafish embryo.
    Nucleic Acids Res. 2004 Dec 07;32(21):6284-91 PMID: 15585662
  33. HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo.
    Blood. 2005 Feb 15;105(4):1456-66 PMID: 15522959
  34. Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells.
    Blood. 2005 Dec 1;106(12):3988-94 PMID: 16091451
  35. Paralogous mouse Hox genes, Hoxa9, Hoxb9, and Hoxd9, function together to control development of the mammary gland in response to pregnancy.
    Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):541-6 PMID: 9892669
  36. Rescue of Drosophila labial null mutant by the chicken ortholog Hoxb-1 demonstrates that the function of Hox genes is phylogenetically conserved.
    Genes Dev. 1996 Jan 15;10(2):176-84 PMID: 8566751
  37. Control of translation and mRNA degradation by miRNAs and siRNAs.
    Genes Dev. 2006 Mar 1;20(5):515-24 PMID: 16510870
  38. Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis.
    Blood. 2007 May 1;109(9):3998-4005 PMID: 17227832
  39. MicroRNAs modulate hematopoietic lineage differentiation.
    Science. 2004 Jan 2;303(5654):83-6 PMID: 14657504
  40. MicroRNA fingerprints during human megakaryocytopoiesis.
    Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5078-83 PMID: 16549775
  41. A mammalian microRNA expression atlas based on small RNA library sequencing.
    Cell. 2007 Jun 29;129(7):1401-14 PMID: 17604727
  42. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis.
    Nature. 2005 Jul 14;436(7048):214-20 PMID: 15951802
  43. HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation.
    Dev Dyn. 2002 May;224(1):58-68 PMID: 11984874
  44. Prediction of mammalian microRNA targets.
    Cell. 2003 Dec 26;115(7):787-98 PMID: 14697198
  45. Murine Hox-1.7 homeo-box gene: cloning, chromosomal location, and expression.
    Mol Cell Biol. 1987 Oct;7(10):3836-41 PMID: 2891029
  46. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.
    Science. 1999 Oct 15;286(5439):531-7 PMID: 10521349
  47. MicroRNA profiling of the murine hematopoietic system.
    Genome Biol. 2005;6(8):R71 PMID: 16086853
  48. Analysis of the murine Hoxa-9 cDNA: an alternatively spliced transcript encodes a truncated protein lacking the homeodomain.
    Gene. 1998 Mar 16;209(1-2):77-85 PMID: 9524228
  49. MicroRNAs and cancer.
    Semin Cancer Biol. 2003 Aug;13(4):253-8 PMID: 14563119
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.01652-07
Email
wfshen@itsa.ucsf.edu
Published
2008-07-00
Epub
2008-00-12
Pages
4609-19
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2447122
Subset
IM
Grants
NCI NIH HHS · R01 CA080029 · United States
NCI NIH HHS · CA80029 · United States
External Links
PubMed source DOI: 10.1128/MCB.01652-07 PMC Full Text View journal details
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