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PMID: 20508144 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells.

Genome research ·Vol. 20 ·No. 8 ·2010-08-00 ·Pages 1052-63

Tallack MR, Whitington T, Yuen WS, Wainwright EN, Keys JR, Gardiner BB, Nourbakhsh E, Cloonan N, Grimmond SM, Bailey TL, Perkins AC

Abstract

KLF1 regulates a diverse suite of genes to direct erythroid cell differentiation from bipotent progenitors. To determine the local cis-regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.5 fetal liver erythroid cells which are occupied by endogenous KLF1. Many of these recovered sites reside in erythroid gene promoters such as Hbb-b1, but the majority are distant to any known gene. Our data suggests KLF1 directly regulates most aspects of terminal erythroid differentiation including production of alpha- and beta-globin protein chains, heme biosynthesis, coordination of proliferation and anti-apoptotic pathways, and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptional activator. Additionally, we suggest new mechanisms for KLF1 cooperation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment.

MeSH Terms
Animals Apoptosis/genetics Base Sequence Cytoskeleton/genetics Erythrocyte Membrane/genetics Erythroid Cells/metabolism Erythropoiesis/genetics GATA1 Transcription Factor/genetics,metabolism Gene Expression Globins/biosynthesis,genetics Heme/biosynthesis,genetics Kruppel-Like Transcription Factors/genetics Mice Molecular Sequence Data Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic
Chemicals
GATA1 Transcription Factor Gata1 protein, mouse Kruppel-Like Transcription Factors erythroid Kruppel-like factor Heme Globins
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Tallack Michael R
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Whitington Tom
Yuen Wai Shan
Wainwright Elanor N
Keys Janelle R
Gardiner Brooke B
Nourbakhsh Ehsan
Cloonan Nicole
Grimmond Sean M
Bailey Timothy L
Perkins Andrew C
References (65)
65 references, click to expand
  1. Functional synergy and physical interactions of the erythroid transcription factor GATA-1 with the Krüppel family proteins Sp1 and EKLF.
    Mol Cell Biol. 1995 May;15(5):2437-47 PMID: 7739528
  2. Discovering novel sequence motifs with MEME.
    Curr Protoc Bioinformatics. 2002 Nov;Chapter 2:Unit 2.4 PMID: 18792935
  3. Apoptotic mechanisms in the control of erythropoiesis.
    Leukemia. 2004 Jul;18(7):1176-99 PMID: 15208642
  4. Sumoylation of EKLF promotes transcriptional repression and is involved in inhibition of megakaryopoiesis.
    Mol Cell Biol. 2007 Dec;27(24):8547-60 PMID: 17938210
  5. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1.
    Nature. 1991 Jan 17;349(6306):257-60 PMID: 1987478
  6. SCL and associated proteins distinguish active from repressive GATA transcription factor complexes.
    Blood. 2009 Mar 5;113(10):2191-201 PMID: 19011221
  7. Activation of Eklf expression during hematopoiesis by Gata2 and Smad5 prior to erythroid commitment.
    Development. 2008 Jun;135(12):2071-82 PMID: 18448565
  8. Chromatin-binding in vivo of the erythroid kruppel-like factor, EKLF, in the murine globin loci.
    Cell Res. 2006 Apr;16(4):347-55 PMID: 16617330
  9. Functional cross-antagonism between transcription factors FLI-1 and EKLF.
    Mol Cell Biol. 2003 Feb;23(4):1390-402 PMID: 12556498
  10. Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy.
    Mol Cell. 2009 Nov 25;36(4):667-81 PMID: 19941826
  11. Functional interaction of GATA1 with erythroid Krüppel-like factor and Sp1 at defined erythroid promoters.
    Blood. 1996 Mar 1;87(5):1793-801 PMID: 8634425
  12. The erythroid phenotype of EKLF-null mice: defects in hemoglobin metabolism and membrane stability.
    Mol Cell Biol. 2005 Jun;25(12):5205-14 PMID: 15923635
  13. Erythroid Krüppel-like factor directly activates the basic Krüppel-like factor gene in erythroid cells.
    Mol Cell Biol. 2007 Apr;27(7):2777-90 PMID: 17283065
  14. A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Krüppel family of nuclear proteins.
    Mol Cell Biol. 1993 May;13(5):2776-86 PMID: 7682653
  15. Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells.
    Nat Genet. 2010 Jan;42(1):53-61 PMID: 20010836
  16. Erythroid Kruppel-like factor (EKLF) coordinates erythroid cell proliferation and hemoglobinization in cell lines derived from EKLF null mice.
    Blood. 2001 Mar 15;97(6):1861-8 PMID: 11238130
  17. Assigning roles to DNA regulatory motifs using comparative genomics.
    Bioinformatics. 2010 Apr 1;26(7):860-6 PMID: 20147307
  18. The active spatial organization of the beta-globin locus requires the transcription factor EKLF.
    Genes Dev. 2004 Oct 15;18(20):2485-90 PMID: 15489291
  19. Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells.
    Blood. 1997 Jan 1;89(1):1-25 PMID: 8978272
  20. Dependence of globin gene expression in mouse erythroleukemia cells on the NF-E2 heterodimer.
    Mol Cell Biol. 1995 Aug;15(8):4640-7 PMID: 7623856
  21. Distinct domains of erythroid Krüppel-like factor modulate chromatin remodeling and transactivation at the endogenous beta-globin gene promoter.
    Mol Cell Biol. 2002 Jan;22(1):161-70 PMID: 11739731
  22. Alterations in expression and chromatin configuration of the alpha hemoglobin-stabilizing protein gene in erythroid Kruppel-like factor-deficient mice.
    Mol Cell Biol. 2006 Jun;26(11):4368-77 PMID: 16705186
  23. UniPROBE: an online database of protein binding microarray data on protein-DNA interactions.
    Nucleic Acids Res. 2009 Jan;37(Database issue):D77-82 PMID: 18842628
  24. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function.
    Trends Pharmacol Sci. 2006 Aug;27(8):402-9 PMID: 16822554
  25. A network of Krüppel-like Factors (Klfs). Klf8 is repressed by Klf3 and activated by Klf1 in vivo.
    J Biol Chem. 2008 Oct 3;283(40):26937-47 PMID: 18687676
  26. Failure of terminal erythroid differentiation in EKLF-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2.
    Mol Cell Biol. 2008 Dec;28(24):7394-401 PMID: 18852285
  27. Locus control regions of mammalian beta-globin gene clusters: combining phylogenetic analyses and experimental results to gain functional insights.
    Gene. 1997 Dec 31;205(1-2):73-94 PMID: 9461381
  28. Human KLF17 is a new member of the Sp/KLF family of transcription factors.
    Genomics. 2006 Apr;87(4):474-82 PMID: 16460907
  29. Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription.
    Nucleic Acids Res. 1998 Jan 15;26(2):512-20 PMID: 9421508
  30. Iron uptake and metabolism in the new millennium.
    Trends Cell Biol. 2007 Feb;17(2):93-100 PMID: 17194590
  31. Chromatin domain activation via GATA-1 utilization of a small subset of dispersed GATA motifs within a broad chromosomal region.
    Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17065-70 PMID: 16286657
  32. Genomic organisation and regulation of murine alpha haemoglobin stabilising protein by erythroid Kruppel-like factor.
    Br J Haematol. 2007 Jan;136(1):150-7 PMID: 17069580
  33. Erythroid Kruppel like factor: from fishing expedition to gourmet meal.
    Int J Biochem Cell Biol. 1999 Oct;31(10):1175-92 PMID: 10582346
  34. GATA-1 forms distinct activating and repressive complexes in erythroid cells.
    EMBO J. 2005 Jul 6;24(13):2354-66 PMID: 15920471
  35. EKLF/KLF1 controls cell cycle entry via direct regulation of E2f2.
    J Biol Chem. 2009 Jul 31;284(31):20966-74 PMID: 19457859
  36. Insights into GATA-1-mediated gene activation versus repression via genome-wide chromatin occupancy analysis.
    Mol Cell. 2009 Nov 25;36(4):682-95 PMID: 19941827
  37. Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression.
    Genome Res. 2009 Dec;19(12):2172-84 PMID: 19887574
  38. Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system.
    Blood. 2003 Dec 1;102(12):3938-46 PMID: 12907435
  39. High-throughput chromatin information enables accurate tissue-specific prediction of transcription factor binding sites.
    Nucleic Acids Res. 2009 Jan;37(1):14-25 PMID: 18988630
  40. Major erythrocyte membrane protein genes in EKLF-deficient mice.
    Exp Hematol. 2006 Jun;34(6):705-12 PMID: 16728274
  41. New insights into erythropoiesis.
    Curr Opin Hematol. 2002 Mar;9(2):93-100 PMID: 11844990
  42. Transcriptional regulation of erythropoiesis: an affair involving multiple partners.
    Oncogene. 2002 May 13;21(21):3368-76 PMID: 12032775
  43. Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene.
    Nature. 1995 May 25;375(6529):316-8 PMID: 7753194
  44. Maturation and enucleation of primitive erythroblasts during mouse embryogenesis is accompanied by changes in cell-surface antigen expression.
    Blood. 2007 Jan 1;109(1):343-52 PMID: 16940424
  45. Erythroid Kruppel-like factor regulates the G1 cyclin dependent kinase inhibitor p18INK4c.
    J Mol Biol. 2007 Jun 1;369(2):313-21 PMID: 17442339
  46. Megakaryocyte-erythroid lineage promiscuity in EKLF null mouse blood.
    Haematologica. 2010 Jan;95(1):144-7 PMID: 19850899
  47. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1.
    Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12355-8 PMID: 8901585
  48. Global regulation of erythroid gene expression by transcription factor GATA-1.
    Blood. 2004 Nov 15;104(10):3136-47 PMID: 15297311
  49. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells.
    Cell. 2008 Jun 13;133(6):1106-17 PMID: 18555785
  50. Ermap, a gene coding for a novel erythroid specific adhesion/receptor membrane protein.
    Gene. 2000 Jan 25;242(1-2):337-45 PMID: 10721728
  51. Long-range chromosomal interactions regulate the timing of the transition between poised and active gene expression.
    EMBO J. 2007 Apr 18;26(8):2041-51 PMID: 17380126
  52. BMP4/Smad5 dependent stress erythropoiesis is required for the expansion of erythroid progenitors during fetal development.
    Dev Biol. 2008 May 1;317(1):24-35 PMID: 18374325
  53. Detection of functional DNA motifs via statistical over-representation.
    Nucleic Acids Res. 2004 Feb 26;32(4):1372-81 PMID: 14988425
  54. The transcriptional program controlled by the stem cell leukemia gene Scl/Tal1 during early embryonic hematopoietic development.
    Blood. 2009 May 28;113(22):5456-65 PMID: 19346495
  55. Analyses of beta-thalassemia mutant DNA interactions with erythroid Krüppel-like factor (EKLF), an erythroid cell-specific transcription factor.
    J Biol Chem. 1994 Jan 14;269(2):1493-500 PMID: 8288615
  56. RNA-MATE: a recursive mapping strategy for high-throughput RNA-sequencing data.
    Bioinformatics. 2009 Oct 1;25(19):2615-6 PMID: 19648138
  57. Statistical significance for genomewide studies.
    Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5 PMID: 12883005
  58. A global map of p53 transcription-factor binding sites in the human genome.
    Cell. 2006 Jan 13;124(1):207-19 PMID: 16413492
  59. E2f4 regulates fetal erythropoiesis through the promotion of cellular proliferation.
    Blood. 2006 Aug 1;108(3):886-95 PMID: 16861343
  60. GATA transcription factors: key regulators of hematopoiesis.
    Exp Hematol. 1995 Feb;23(2):99-107 PMID: 7828675
  61. neptune, a Krüppel-like transcription factor that participates in primitive erythropoiesis in Xenopus.
    Curr Biol. 2001 Sep 18;11(18):1456-61 PMID: 11566106
  62. Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein.
    Nature. 1993 Apr 22;362(6422):722-8 PMID: 8469283
  63. A global role for EKLF in definitive and primitive erythropoiesis.
    Blood. 2006 Apr 15;107(8):3359-70 PMID: 16380451
  64. Deregulated E2f-2 underlies cell cycle and maturation defects in retinoblastoma null erythroblasts.
    Mol Cell Biol. 2007 Dec;27(24):8713-28 PMID: 17923680
  65. Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF.
    Nature. 1995 May 25;375(6529):318-22 PMID: 7753195
Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1549-5469
DOI
10.1101/gr.106575.110
Published
2010-08-00
Epub
2010-00-27
Pages
1052-63
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC2909569
Subset
IM
Databases
GEO
GSE20478
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1101/gr.106575.110 PMC Full Text View journal details
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