Chromatin and the Control of Hox Gene Expression

  • Laila Kobrossy
  • Mark Featherstone


Antero-posterior patterning of the animal embryo is governed in part by the highly conserved Hox genes. In most animals studied to date, Hox genes are assembled within one or more clusters.1, 2, 3, 4, 5 The thirty-nine Hox genes of mice and humans are organized into four clusters, each located on a different chromosome.4 There are thirteen possible gene positions in each cluster, although none of the clusters retains all thirteen members (Fig. 1). Hox genes occupying the same relative position between clusters are termed paralogs, sharing high sequence identity and functional redundancy. Because all genes are transcribed in the same direction, one can assign a 3′ and a 5′ end to a cluster.


Chromosomal Territory Promyelocytic Leukemia Zinc Finger Homeotic Transformation Retinoic Acid Response Element HoxD Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    McGinnis W, Hart CP, Gehring WJ et al. Molecular cloning and chromosome mapping of a mouse DNA sequence homologous to homeotic genes of Drosophila. Cell 1984; 38(3):675–680.PubMedCrossRefGoogle Scholar
  2. 2.
    McGinnis W, Levine MS, Hafen E et al. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. Nature 1984; 308(5958):428–433.PubMedCrossRefGoogle Scholar
  3. 3.
    Scott MP, Weiner AJ. Structural relationships among genes that control development: Sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila. Proc Natl Acad Sci USA 1984; 81(13):4115–4119.PubMedCrossRefGoogle Scholar
  4. 4.
    Krumlauf R. Hox genes in vertebrate development. Cell 1994; 78(2):191–201.PubMedCrossRefGoogle Scholar
  5. 5.
    Kappen C, Schughart K, Ruddle FH. Organization and expression of homeobox genes in mouse and man. Ann NY Acad Sci 1989; 567:243–252.PubMedCrossRefGoogle Scholar
  6. 6.
    Manzanares M, Wada H, Itasaki N et al. Conservation and elaboration of Hox gene regulation during evolution of the vertebrate head. Nature 2000; 408(6814):854–857.PubMedCrossRefGoogle Scholar
  7. 7.
    de la Serna IL, Ohkawa Y, Imbalzano AN. Chromatin remodelling in mammalian differentiation: Lessons from ATP-dependent remodellers. Nat Rev Genet 2006; 7(6):461–473.PubMedCrossRefGoogle Scholar
  8. 8.
    Featherstone M. Coactivators in transcription initiation: Here are your orders. Curr Opin Genet Dev 2002; 12(2):149–155.PubMedCrossRefGoogle Scholar
  9. 9.
    Fischle W, Wang Y, Allis CD. Histone and chromatin cross-talk. Curr Opin Cell Biol 2003; 15(2):172–183.PubMedCrossRefGoogle Scholar
  10. 10.
    Roth SY, Denu JM, Allis CD. Histone acetyltransferases. Annu Rev Biochem 2001; 70:81–120.PubMedCrossRefGoogle Scholar
  11. 11.
    Yang XJ, Seto E. Collaborative spirit of histone deacetylases in regulating chromatin structure and gene expression. Curr Opin Genet Dev 2003; 13(2):143–153.PubMedCrossRefGoogle Scholar
  12. 12.
    Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293(5532):1074–1080.PubMedCrossRefGoogle Scholar
  13. 13.
    Kmita M, Duboule D. Organizing axes in time and space; 25 years of colinear tinkering. Science 2003; 301(5631):331–333.PubMedCrossRefGoogle Scholar
  14. 14.
    Lufkin T, Mark M, Hart CP et al. Homeotic transformation of the occipital bones of the skull by ectopic expression of a homeobox gene. Nature 1992; 359(6398):835–841.PubMedCrossRefGoogle Scholar
  15. 15.
    Duboule D. Vertebrate hox gene regulation: Clustering and/or colinearity? Curr Opin Genet Dev 1998; 8(5):514–518.PubMedCrossRefGoogle Scholar
  16. 16.
    Duboule D, Deschamps J. Colinearity loops out. Dev Cell 2004; 6(6):738–740.PubMedCrossRefGoogle Scholar
  17. 17.
    Roelen BA, de Graaff W, Forlani S et al. Hox cluster polarity in early transcriptional availability: A high order regulatory level of clustered Hox genes in the mouse. Mech Dev 2002; 119(1):81–90.PubMedCrossRefGoogle Scholar
  18. 18.
    Deschamps J, van Nes J. Developmental regulation of the Hox genes during axial morphogenesis in the mouse. Development 2005; 132(13):2931–2942.PubMedCrossRefGoogle Scholar
  19. 19.
    Rastegar M, Kobrossy L, Kovacs EN et al. Sequential histone modifications at Hoxd4 regulatory regions distinguish anterior from posterior embryonic compartments. Mol Cell Biol 2004; 24(18):8090–8103.PubMedCrossRefGoogle Scholar
  20. 20.
    Bickmore WA, Mahy NL, Chambeyron S. Do higher-order chromatin structure and nuclear reorganization play a role in regulating Hox gene expression during development? Cold Spring Harb Symp Quant Biol 2004; 69:251–257.PubMedCrossRefGoogle Scholar
  21. 21.
    Chambeyron S, Bickmore WA. Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. Genes Dev 2004; 18(10):1119–1130.PubMedCrossRefGoogle Scholar
  22. 22.
    Cirillo LA, Lin FR, Cuesta I et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol Cell 2002; 9(2):279–289.PubMedCrossRefGoogle Scholar
  23. 23.
    Berkes CA, Bergstrom DA, Penn BH et al. Pbx marks genes for activation by MyoD indicating a role for a homeodomain protein in establishing myogenic potential. Mol Cell 2004; 14(4):465–477.PubMedCrossRefGoogle Scholar
  24. 24.
    Weston AD, Blumberg B, Underhill TM. Active repression by unliganded retinoid receptors in development: Less is sometimes more. J Cell Biol 2003; 161(2):223–228.PubMedCrossRefGoogle Scholar
  25. 25.
    Tarchini B, Duboule D. Control of Hoxd genes’ collinearity during early limb development. Dev Cell 2006; 10(1):93–103.PubMedCrossRefGoogle Scholar
  26. 26.
    Weston AD, Hoffman LM, Underhill TM. Revisiting the role of retinoid signaling in skeletal development. Birth Defects Res C Embryo Today 2003; 69(2):156–173.PubMedCrossRefGoogle Scholar
  27. 27.
    Dupé V, Davenne M, Brocard J et al. In vivo functional analysis of the Hoxa-1 3′ retinoic acid response element (3′RARE). Development 1997; 124(2):399–410.PubMedGoogle Scholar
  28. 28.
    Gould A, Itasaki N, Krumlauf R. Initiation of rhombomeric Hoxb4 expression requires induction by somites and a retinoid pathway. Neuron 1998; 21(1):39–51.PubMedCrossRefGoogle Scholar
  29. 29.
    Huang D, Chen SW, Gudas LJ. Analysis of two distinct retinoic acid response elements in the homeobox gene Hoxb1 in transgenic mice. Dev Dyn 2002; 223(3):353–370.PubMedCrossRefGoogle Scholar
  30. 30.
    Langston AW, Gudas LJ. Identification of a retinoic acid responsive enhancer 3′ of the murine homeobox gene Hox-1.6. Mech Dev 1992; 38(3):217–227.PubMedCrossRefGoogle Scholar
  31. 31.
    Marshall H, Studer M, Popped H et al. A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1. Nature 1994; 370(6490):567–571.PubMedCrossRefGoogle Scholar
  32. 32.
    Packer AI, Crotty DA, Elwell VA et al. Expression of the murine Hoxa4 gene requires both auto-regulation and a conserved retinoic acid response element. Development 1998; 125(11):1991–1998.PubMedGoogle Scholar
  33. 33.
    Studer M, Popped H, Marshall H et al. Role of a conserved retinoic acid response element in rhombomere restriction of Hoxb-1. Science 1994; 265(5179):1728–1732.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang F, Nagy Kovacs E, Featherstone MS. Murine hoxd4 expression in the CNS requires multiple elements including a retinoic acid response element. Mech Dev 2000; 96(1):79–89.PubMedCrossRefGoogle Scholar
  35. 35.
    Oosterveen T, Niederreither K, Dolle P et al. Retinoids regulate the anterior expression boundaries of 5′ Hoxb genes in posterior hindbrain. EMBO J 2003; 22(2):262–269.PubMedCrossRefGoogle Scholar
  36. 36.
    van der Hoeven F, Zákány J, Duboule D. Gene transpositions in the HoxD complex reveal a hierarchy of regulatory controls. Cell 1996; 85(7):1025–1035.PubMedCrossRefGoogle Scholar
  37. 37.
    Kondo T, Duboule D. Breaking colinearity in the mouse HoxD complex. Cell 1999; 97(3):407–417.PubMedCrossRefGoogle Scholar
  38. 38.
    Barna M, Merghoub T, Costoya JA et al. Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling. Dev Cell 2002; 3(4):499–510.PubMedCrossRefGoogle Scholar
  39. 39.
    Chambeyron S, Da Silva NR, Lawson KA et al. Nuclear reorganisation of the Hoxb complex during mouse embryonic development. Development 2005; 132(9):2215–2223.PubMedCrossRefGoogle Scholar
  40. 40.
    Kobrossy L, Rastegar M, Featherstone M. Interplay between chromatin and trans-acting factors regulating the Hoxd4 promoter during neural differentiation. J Biol Chem 2006.Google Scholar
  41. 41.
    Narlikar GJ, Fan HY, Kingston RE. Cooperation between complexes that regulate chromatin structure and transcription. Cell 2002; 108(4):475–487.PubMedCrossRefGoogle Scholar
  42. 42.
    Meccia E, Bottero L, Felicetti F et al. HOXB7 expression is regulated by the transcription factors NF-Y, YY1, Sp1 and USF-1. Biochim Biophys Acta 2003; 1626(1–3):1–9.PubMedGoogle Scholar
  43. 43.
    Gilthorpe J, Vandromme M, Brend T et al. Spatially specific expression of Hoxb4 is dependent on the ubiquitous transcription factor NFY. Development 2002; 129(16):3887–3899.PubMedGoogle Scholar
  44. 44.
    Bernstein BE, Kamal M, Lindblad-Toh K et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 2005; 120(2):169–181.PubMedCrossRefGoogle Scholar
  45. 45.
    Kennison JA. The Polycomb and trithorax group proteins of Drosophila: Trans-regulators of homeotic gene function. Annu Rev Genet 1995; 29:289–303.PubMedCrossRefGoogle Scholar
  46. 46.
    Shao Z, Raible F, Mollaaghababa R et al. Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 1999; 98(1):37–46.PubMedCrossRefGoogle Scholar
  47. 47.
    Saurin AJ, Shao Z, Erdjument-Bromage H et al. A Drosophila Polycomb group complex includes Zeste and dTAFII proteins. Nature 2001; 412(6847):655–660.PubMedCrossRefGoogle Scholar
  48. 48.
    Satijn DP, Otte AP. Polycomb group protein complexes: Do different complexes regulate distinct target genes? Biochim Biophys Acta 1999; 1447(1):1–16.PubMedGoogle Scholar
  49. 49.
    Francis NJ, Saurin AJ, Shao Z et al. Reconstitution of a functional core polycomb repressive complex. Mol Cell 2001; 8(3):545–556.PubMedCrossRefGoogle Scholar
  50. 50.
    Levine SS, Weiss A, Erdjument-Bromage H et al. The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans. Mol Cell Biol 2002; 22(17):6070–6078.PubMedCrossRefGoogle Scholar
  51. 51.
    Tie F, Furuyama T, Prasad-Sinha J et al. The Drosophila Polycomb Group proteins ESC and E(Z) are present in a complex containing the histone-binding protein p55 and the histone deacetylase RPD3. Development 2001; 128(2):275–286.PubMedGoogle Scholar
  52. 52.
    Ng J, Hart CM, Morgan K et al. A Drosophila ESC-E(Z) protein complex is distinct from other polycomb group complexes and contains covalently modified ESC. Mol Cell Biol 2000; 20(9):3069–3078.PubMedCrossRefGoogle Scholar
  53. 53.
    Cao R, Wang L, Wang H et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 2002; 298(5595):1039–1043.PubMedCrossRefGoogle Scholar
  54. 54.
    Czermin B, Melfi R, McCabe D et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 2002; 111(2):185–196.PubMedCrossRefGoogle Scholar
  55. 55.
    Kuzmichev A, Nishioka K, Erdjument-Bromage H et al. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev 2002; 16(22):2893–2905.PubMedCrossRefGoogle Scholar
  56. 56.
    Muller J, Hart CM, Francis NJ et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 2002; 111(2):197–208.PubMedCrossRefGoogle Scholar
  57. 57.
    Rastelli L, Chan CS, Pirrotta V. Related chromosome binding sites for zeste, suppressors of zeste and Polycomb group proteins in Drosophila and their dependence on Enhancer of zeste function. EMBO J 1993; 12(4):1513–1522.PubMedGoogle Scholar
  58. 58.
    Poux S, McCabe D, Pirrotta V. Recruitment of components of Polycomb Group chromatin complexes in Drosophila. Development 2001; 128(1):75–85.PubMedGoogle Scholar
  59. 59.
    Simon JA, Tamkun JW. Programming off and on states in chromatin: Mechanisms of Polycomb and trithorax group complexes. Curr Opin Genet Dev 2002; 12(2):210–218.PubMedCrossRefGoogle Scholar
  60. 60.
    Tagawa M, Sakamoto T, Shigemoto K et al. Expression of novel DNA-binding protein with zinc finger structure in various tumor cells. J Biol Chem 1990; 265(32):20021–20026.PubMedGoogle Scholar
  61. 61.
    van Lohuizen M, Frasch M, Wientjens E et al. Sequence similarity between the mammalian bmi-1 proto-oncogene and the Drosophila regulatory genes Psc and Su(z)2. Nature 1991; 353(6342):353–355.PubMedCrossRefGoogle Scholar
  62. 62.
    Pearce JJ, Singh PB, Gaunt SJ. The mouse has a Polycomb-like chromobox gene. Development 1992; 114(4):921–929.PubMedGoogle Scholar
  63. 63.
    Satijn DP, Olson DJ, van der Vlag J et al. Interference with the expression of a novel human polycomb protein, hPc2, results in cellular transformation and apoptosis. Mol Cell Biol 1997; 17(10):6076–6086.PubMedGoogle Scholar
  64. 64.
    Gunster MJ, Satijn DP, Hamer KM et al. Identification and characterization of interactions between the vertebrate polycomb-group protein BMI1 and human homologs of polyhomeotic. Mol Cell Biol 1997; 17(4):2326–2335.PubMedGoogle Scholar
  65. 65.
    Hemenway CS, Halligan BW, Levy LS. The Bmi-1 oncoprotein interacts with dinG and MPh2: The role of RING finger domains. Oncogene 1998; 16(19):2541–2547.PubMedCrossRefGoogle Scholar
  66. 66.
    Schoorlemmer J, Marcos-Gutierrez C, Were F et al. RinglA is a transcriptional repressor that interacts with the Polycomb-M33 protein and is expressed at rhombomere boundaries in the mouse hindbrain. EMBO J 1997; 16(19):5930–5942.PubMedCrossRefGoogle Scholar
  67. 67.
    Akasaka T, Kanno M, Balling R et al. A role for mel-18, a Polycomb group-related vertebrate gene, during theanteroposterior specification of the axial skeleton. Development 1996; 122(5):1513–1522.PubMedGoogle Scholar
  68. 68.
    van der Lugt NM, Alkema M, Berns A et al. The Polycomb-group homolog Bmi-1 is a regulator of murine Hox gene expression. Mech Dev 1996; 58(1–2):153–164.PubMedGoogle Scholar
  69. 69.
    Suzuki M, Mizutani-Koseki Y, Fujimura Y et al. Involvement of the Polycomb-group gene RinglB in the specification of the anterior-posterior axis in mice. Development 2002; 129(18):4171–4183.PubMedGoogle Scholar
  70. 70.
    Akasaka T, van Lohuizen M, van der Lugt N et al. Mice doubly deficient for the Polycomb Group genes Mel 18 and Bmil reveal synergy and requirement for maintenance but not initiation of Hox gene expression. Development 2001; 128(9):1587–1597.PubMedGoogle Scholar
  71. 71.
    Isono K, Fujimura Y, Shinga J et al. Mammalian polyhomeotic homologues Phc2 and Phcl act in synergy to mediate polycomb repression of Hox genes. Mol Cell Biol 2005; 25(15):6694–6706.PubMedCrossRefGoogle Scholar
  72. 72.
    Fujimura Y, Koseki H. Role of mammalian polycomb group gene products in embryo genesis. Tanpakushitsu Kakusan Koso 2005; 50(6 Suppl):563–568.PubMedGoogle Scholar
  73. 73.
    de Graaff W, Tomotsune D, Oosterveen T et al. Randomly inserted and targeted Hox/reporter fusions transcriptionally silenced in Polycomb mutants. Proc Natl Acad Sci USA 2003; 100(23):13362–13367.CrossRefGoogle Scholar
  74. 74.
    Luo L, Kessel M. Geminin coordinates cell cycle and developmental control. Cell Cycle 2004; 3(6):711–714.PubMedGoogle Scholar
  75. 75.
    Luo L, Yang X, Takihara Y et al. The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions. Nature 2004; 427(6976):749–753.PubMedCrossRefGoogle Scholar
  76. 76.
    Papoulas O, Beek SJ, Moseley SL et al. The Drosophila trithorax group proteins BRM, ASH1 and ASH2 are subunits of distinct protein complexes. Development 1998; 125(20):3955–3966.PubMedGoogle Scholar
  77. 77.
    Petruk S, Sedkov Y, Smith S et al. Trithorax and dCBP acting in a complex to maintain expression of a homeotic gene. Science 2001; 294(5545):1331–1334.PubMedCrossRefGoogle Scholar
  78. 78.
    Lachner M, O’Carroll D, Rea S et al. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 2001; 410(6824):116–120.PubMedCrossRefGoogle Scholar
  79. 79.
    Zhang Y, Reinberg D. Transcription regulation by histone methylation: Interplay between different covalent modifications of the core histone tails. Genes Dev 2001; 15(18):2343–2360.PubMedCrossRefGoogle Scholar
  80. 80.
    Kal AJ, Mahmoudi T, Zak NB et al. The Drosophila brahma complex is an essential coactivator for the trithorax group protein zeste. Genes Dev 2000; 14(9):1058–1071.PubMedGoogle Scholar
  81. 81.
    Sobulo OM, Borrow J, Tomek R et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11; 16)(q23; p13.3). Proc Natl Acad Sci USA 1997; 94(16):8732–8737.PubMedCrossRefGoogle Scholar
  82. 82.
    Lavau C, Du C, Thirman M et al. Chromatin-related properties of CBP fused to MLL generate a myelodysplastic-like syndrome that evolves into myeloid leukemia. EMBO J 2000; 19(17):4655–4664.PubMedCrossRefGoogle Scholar
  83. 83.
    Hess JL. Mechanisms of transformation by MLL. Crit Rev Eukaryot Gene Expr 2004; 14(4):235–254.PubMedCrossRefGoogle Scholar
  84. 84.
    Milne TA, Briggs SD, Brock HW et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 2002; 10(5):1107–1117.PubMedCrossRefGoogle Scholar
  85. 85.
    Dou Y, Milne TA, Tackett AJ et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 2005; 121(6):873–885.PubMedCrossRefGoogle Scholar
  86. 86.
    Yu BD, Hess JL, Horning SE et al. Altered Hox expression and segmental identity in Mil-mutant mice. Nature 1995; 378(6556):505–508.PubMedCrossRefGoogle Scholar
  87. 87.
    Milne TA, Dou Y, Martin ME et al. MLL associates specifically with a subset of transcriptionally active target genes. Proc Natl Acad Sci USA 2005; 102(41):14765–14770.PubMedCrossRefGoogle Scholar
  88. 88.
    Terranova R, Agherbi H, Boned A et al. Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of M11. Proc Natl Acad Sci USA 2006; 103(17):6629–6634.PubMedCrossRefGoogle Scholar
  89. 89.
    Marks PA, Richon VM, Miller T et al. Histone deacetylase inhibitors. Adv Cancer Res 2004; 91:137–168.PubMedCrossRefGoogle Scholar
  90. 90.
    Core N, Bel S, Gaunt SJ et al. Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development 1997; 124(3):721–729.PubMedGoogle Scholar
  91. 91.
    Bel S, Core N, Djabali M et al. Genetic interactions and dosage effects of Polycomb group genes in mice. Development 1998; 125(18):3543–3551.PubMedGoogle Scholar

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© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  1. 1.Department of Molecular and Cellular BiologyHarvard UniversityCambridgeUSA
  2. 2.School of Biological SciencesNanyang Technological UniversitySingaporeRepublic of Singapore

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