Bipartite Recognition of DNA by TCF/Pangolin Is Remarkably Flexible and Contributes to Transcriptional Responsiveness and Tissue Specificity of Wingless Signaling

English version České info

Regulation of gene expression is controlled in large part by proteins known as transcription factors, which bind to specific DNA sequences in the genome. The DNA binding domains of transcription factors recognize short stretches (5–11 base pairs) of DNA with considerable sequence degeneracy. This means that a single DNA binding domain, on its own, cannot find its targets in the vast excess of genomic sequence. We are studying this question using TCF/Pangolin, a Drosophila transcription factor that mediates Wnt/β-catenin signaling, an important developmental cell-cell communication pathway. TCF/Pangolin contains two DNA binding domains that bind to a pair of DNA motifs known as HMG and Helper sites. We used a combination of biochemistry, genetics and bioinformatics to elucidate the spacing and orientation constraints of HMG-Helper site pairs. We found that HMG-Helper site spacing/orientation influenced the sensitivity of a target to Wnt signaling, as well as its tissue-responsiveness. We used this information to improve our ability to search the Drosophila genome for Wnt targets, one of which was activated by the pathway in the fly ring gland, the major endocrine organ in insects. Our work is relevant to related mammalian TCF family members, which are implicated in development, stem cell biology and the progression of cancer.

Vyšlo v časopise: Bipartite Recognition of DNA by TCF/Pangolin Is Remarkably Flexible and Contributes to Transcriptional Responsiveness and Tissue Specificity of Wingless Signaling. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004591
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004591

Souhrn

Zdroje

1. ArchboldHC, YangYX, ChenL, CadiganKM (2012) How do they do Wnt they do: regulation of transcription by the Wnt/beta-catenin pathway. Acta Physiol (Oxf) 204: 74–109.

2. CadiganKM, NusseR (1997) Wnt signaling: a common theme in animal development. Genes Dev 11: 3286–3305.

3. CleversH (2006) Wnt/beta-catenin signaling in development and disease. Cell 127: 469–480.

4. GrigoryanT, WendP, KlausA, BirchmeierW (2008) Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev 22: 2308–2341.

5. GessertS, KuhlM (2010) The multiple phases and faces of wnt signaling during cardiac differentiation and development. Circ Res 107: 186–199.

6. LiuF, MillarSE (2010) Wnt/beta-catenin signaling in oral tissue development and disease. J Dent Res 89: 318–330.

7. NiehrsC (2010) On growth and form: a Cartesian coordinate system of Wnt and BMP signaling specifies bilaterian body axes. Development 137: 845–857.

8. TowersM, WolpertL, TickleC (2012) Gradients of signalling in the developing limb. Curr Opin Cell Biol 24: 181–187.

9. PerrimonN, PitsouliC, ShiloBZ (2012) Signaling mechanisms controlling cell fate and embryonic patterning. Cold Spring Harb Perspect Biol 4: a005975.

10. Sanchez-CamachoC, BovolentaP (2009) Emerging mechanisms in morphogen-mediated axon guidance. Bioessays 31: 1013–1025.

11. SwarupS, VerheyenEM (2012) Wnt/Wingless signaling in Drosophila. Cold Spring Harb Perspect Biol 4: a007930.

12. ArceL, YokoyamaNN, WatermanML (2006) Diversity of LEF/TCF action in development and disease. Oncogene 25: 7492–7504.

13. BarkerN, TanS, CleversH (2013) Lgr proteins in epithelial stem cell biology. Development 140: 2484–2494.

14. HollandJD, KlausA, GarrattAN, BirchmeierW (2013) Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol 25: 254–264.

15. LimX, NusseR (2013) Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harb Perspect Biol 5: a008029.

16. SatoT, CleversH (2013) Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340: 1190–1194.

17. JoinerDM, KeJ, ZhongZ, XuHE, WilliamsBO (2013) LRP5 and LRP6 in development and disease. Trends Endocrinol Metab 24: 31–39.

18. PolakisP (2012) Wnt signaling in cancer. Cold Spring Harb Perspect Biol 4: a008052.

19. RegardJB, ZhongZ, WilliamsBO, YangY (2012) Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harb Perspect Biol 4: a007997.

20. BrantjesH, BarkerN, van EsJ, CleversH (2002) TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling. Biol Chem 383: 255–261.

21. CadiganKM, WatermanML (2012) TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 4: a007906.

22. CadiganKM (2012) TCFs and Wnt/beta-catenin signaling: more than one way to throw the switch. Curr Top Dev Biol 98: 1–34.

23. ValentaT, HausmannG, BaslerK (2012) The many faces and functions of beta-catenin. EMBO J 31: 2714–2736.

24. BlahnikKR, DouL, O'GeenH, McPhillipsT, XuX, et al. (2010) Sole-Search: an integrated analysis program for peak detection and functional annotation using ChIP-seq data. Nucleic Acids Res 38: e13.

25. BottomlyD, KylerSL, McWeeneySK, YochumGS (2010) Identification of {beta}-catenin binding regions in colon cancer cells using ChIP-Seq. Nucleic Acids Res 38: 5735–5745.

26. ColeMF, JohnstoneSE, NewmanJJ, KageyMH, YoungRA (2008) Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev 22: 746–755.

27. FrietzeS, WangR, YaoL, TakYG, YeZ, et al. (2012) Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3. Genome Biol 13: R52.

28. JunionG, SpivakovM, GirardotC, BraunM, GustafsonEH, et al. (2012) A transcription factor collective defines cardiac cell fate and reflects lineage history. Cell 148: 473–486.

29. TrompoukiE, BowmanTV, LawtonLN, FanZP, WuDC, et al. (2011) Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell 147: 577–589.

30. VerziMP, HatzisP, SulahianR, PhilipsJ, SchuijersJ, et al. (2010) TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions. Proceedings of the National Academy of Sciences of the United States of America 107: 15157–15162.

31. WuJQ, SeayM, SchulzVP, HariharanM, TuckD, et al. (2012) Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line. PLoS Genet 8: e1002565.

32. BlauwkampTA, ChangMV, CadiganKM (2008) Novel TCF-binding sites specify transcriptional repression by Wnt signalling. EMBO J 27: 1436–1446.

33. Zhang CUBT, BurbyPE, CadiganKM (2014) Wnt-mediated repression via bipartite DNA recognition by TCF in the Drosophila hematopoietic system. PLoS Genetics In Press.

34. GieseK, AmsterdamA, GrosschedlR (1991) DNA-binding properties of the HMG domain of the lymphoid-specific transcriptional regulator LEF-1. Genes Dev 5: 2567–2578.

35. HallikasO, PalinK, SinjushinaN, RautiainenR, PartanenJ, et al. (2006) Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell 124: 47–59.

36. van BeestM, DooijesD, van De WeteringM, KjaerulffS, BonvinA, et al. (2000) Sequence-specific high mobility group box factors recognize 10–12-base pair minor groove motifs. J Biol Chem 275: 27266–27273.

37. van de WeteringM, OosterwegelM, DooijesD, CleversH (1991) Identification and cloning of TCF-1, a T lymphocyte-specific transcription factor containing a sequence-specific HMG box. EMBO J 10: 123–132.

38. BaroloS (2006) Transgenic Wnt/TCF pathway reporters: all you need is Lef? Oncogene 25: 7505–7511.

39. DasGuptaR, KaykasA, MoonRT, PerrimonN (2005) Functional genomic analysis of the Wnt-wingless signaling pathway. Science 308: 826–833.

40. KorinekV, BarkerN, MorinPJ, van WichenD, de WegerR, et al. (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science 275: 1784–1787.

41. LumL, YaoS, MozerB, RovescalliA, Von KesslerD, et al. (2003) Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299: 2039–2045.

42. GengX, XiaoL, LinGF, HuR, WangJH, et al. (2003) Lef/Tcf-dependent Wnt/beta-catenin signaling during Xenopus axis specification. FEBS Lett 547: 1–6.

43. DessimozJ, BonnardC, HuelskenJ, Grapin-BottonA (2005) Pancreas-specific deletion of beta-catenin reveals Wnt-dependent and Wnt-independent functions during development. Curr Biol 15: 1677–1683.

44. ChangMV, ChangJL, GangopadhyayA, ShearerA, CadiganKM (2008) Activation of wingless targets requires bipartite recognition of DNA by TCF. Curr Biol 18: 1877–1881.

45. AtchaFA, SyedA, WuB, HoverterNP, YokoyamaNN, et al. (2007) A unique DNA binding domain converts T-cell factors into strong Wnt effectors. Mol Cell Biol 27: 8352–8363.

46. HoverterNP, TingJH, SundareshS, BaldiP, WatermanML (2012) A WNT/p21 circuit directed by the C-clamp, a sequence-specific DNA binding domain in TCFs. Mol Cell Biol 32: 3648–3662.

47. WallmenB, SchremppM, HechtA (2012) Intrinsic properties of Tcf1 and Tcf4 splice variants determine cell-type-specific Wnt/beta-catenin target gene expression. Nucleic Acids Res 40: 9455–9469.

48. RavindranathAJ, CadiganKM (2014) Structure-Function Analysis of the C-clamp of TCF/Pangolin in Wnt/ß-catenin signaling. PLoS ONE 9: e91378.

49. NaarAM, BoutinJM, LipkinSM, YuVC, HollowayJM, et al. (1991) The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors. Cell 65: 1267–1279.

50. KatzRW, KoenigRJ (1994) Nucleotide substitutions differentially affect direct repeat and palindromic thyroid hormone response elements. J Biol Chem 269: 9500–9505.

51. PhanTQ, JowMM, PrivalskyML (2010) DNA recognition by thyroid hormone and retinoic acid receptors: 3,4,5 rule modified. Mol Cell Endocrinol 319: 88–98.

52. PyrowolakisG, HartmannB, MullerB, BaslerK, AffolterM (2004) A simple molecular complex mediates widespread BMP-induced repression during Drosophila development. Dev Cell 7: 229–240.

53. WeissA, CharbonnierE, EllertsdottirE, TsirigosA, WolfC, et al. (2010) A conserved activation element in BMP signaling during Drosophila development. Nat Struct Mol Biol 17: 69–76.

54. DawsonSJ, LiuYZ, RodelB, MoroyT, LatchmanDS (1996) The ability of POU family transcription factors to activate or repress gene expression is dependent on the spacing and context of their specific response elements. Biochem J 314 (Pt 2) 439–443.

55. ScullyKM, JacobsonEM, JepsenK, LunyakV, ViadiuH, et al. (2000) Allosteric effects of Pit-1 DNA sites on long-term repression in cell type specification. Science 290: 1127–1131.

56. RemacleJE, KraftH, LerchnerW, WuytensG, CollartC, et al. (1999) New mode of DNA binding of multi-zinc finger transcription factors: deltaEF1 family members bind with two hands to two target sites. EMBO J 18: 5073–5084.

57. ChangJL, ChangMV, BaroloS, CadiganKM (2008) Regulation of the feedback antagonist naked cuticle by Wingless signaling. Dev Biol 321: 446–454.

58. van de WeteringM, CavalloR, DooijesD, van BeestM, van EsJ, et al. (1997) Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88: 789–799.

59. BischofJ, MaedaRK, HedigerM, KarchF, BaslerK (2007) An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases. Proc Natl Acad Sci U S A 104: 3312–3317.

60. BakerNE (1988) Localization of transcripts from the wingless gene in whole Drosophila embryos. Development 103: 289–298.

61. CousoJP, BateM, Martinez-AriasA (1993) A wingless-dependent polar coordinate system in Drosophila imaginal discs. Science 259: 484–489.

62. PhillipsRG, WhittleJR (1993) wingless expression mediates determination of peripheral nervous system elements in late stages of Drosophila wing disc development. Development 118: 427–438.

63. BejsovecA, Martinez AriasA (1991) Roles of wingless in patterning the larval epidermis of Drosophila. Development 113: 471–485.

64. KlingensmithJ, NusseR (1994) Signaling by wingless in Drosophila. Dev Biol 166: 396–414.

65. LawrencePA, BodmerR, VincentJP (1995) Segmental patterning of heart precursors in Drosophila. Development 121: 4303–4308.

66. ParkM, WuX, GoldenK, AxelrodJD, BodmerR (1996) The wingless signaling pathway is directly involved in Drosophila heart development. Dev Biol 177: 104–116.

67. SosinskyA, BoninCP, MannRS, HonigB (2003) Target Explorer: An automated tool for the identification of new target genes for a specified set of transcription factors. Nucleic Acids Res 31: 3589–3592.

68. WodarzA, HinzU, EngelbertM, KnustE (1995) Expression of crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila. Cell 82: 67–76.

69. CoxRT, KirkpatrickC, PeiferM (1996) Armadillo is required for adherens junction assembly, cell polarity, and morphogenesis during Drosophila embryogenesis. J Cell Biol 134: 133–148.

70. TepassU, Gruszynski-DeFeoE, HaagTA, OmatyarL, TorokT, et al. (1996) shotgun encodes Drosophila E-cadherin and is preferentially required during cell rearrangement in the neurectoderm and other morphogenetically active epithelia. Genes Dev 10: 672–685.

71. BhanotP, FishM, JemisonJA, NusseR, NathansJ, et al. (1999) Frizzled and Dfrizzled-2 function as redundant receptors for Wingless during Drosophila embryonic development. Development 126: 4175–4186.

72. HackerU, GrossniklausU, GehringWJ, JackleH (1992) Developmentally regulated Drosophila gene family encoding the fork head domain. Proc Natl Acad Sci U S A 89: 8754–8758.

73. GibbensYY, WarrenJT, GilbertLI, O'ConnorMB (2011) Neuroendocrine regulation of Drosophila metamorphosis requires TGFbeta/Activin signaling. Development 138: 2693–2703.

74. McGuireSE, MaoZ, DavisRL (2004) Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila. Sci STKE 2004: pl6.

75. ZhouB, BagriA, BeckendorfSK (2001) Salivary gland determination in Drosophila: a salivary-specific, fork head enhancer integrates spatial pattern and allows fork head autoregulation. Dev Biol 237: 54–67.

76. HochM, PankratzMJ (1996) Control of gut development by fork head and cell signaling molecules in Drosophila. Mech Dev 58: 3–14.

77. BulowMH, AebersoldR, PankratzMJ, JungerMA (2010) The Drosophila FoxA ortholog Fork head regulates growth and gene expression downstream of Target of rapamycin. PLoS One 5: e15171.

78. BhambhaniC, RavindranathAJ, MentinkRA, ChangMV, BetistMC, et al. (2014) Distinct DNA Binding Sites Contribute to the TCF Transcriptional Switch in C. elegans and Drosophila. PLoS Genetics 10: 31004133.

79. MeijsingSH, PufallMA, SoAY, BatesDL, ChenL, et al. (2009) DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324: 407–410.

80. LoveJJ, LiX, CaseDA, GieseK, GrosschedlR, et al. (1995) Structural basis for DNA bending by the architectural transcription factor LEF-1. Nature 376: 791–795.

81. BaegGH, LinX, KhareN, BaumgartnerS, PerrimonN (2001) Heparan sulfate proteoglycans are critical for the organization of the extracellular distribution of Wingless. Development 128: 87–94.

82. CadiganKM, FishMP, RulifsonEJ, NusseR (1998) Wingless repression of Drosophila frizzled 2 expression shapes the Wingless morphogen gradient in the wing. Cell 93: 767–777.

83. StriginiM, CohenSM (2000) Wingless gradient formation in the Drosophila wing. Curr Biol 10: 293–300.

84. ZeccaM, BaslerK, StruhlG (1996) Direct and long-range action of a wingless morphogen gradient. Cell 87: 833–844.

85. JiangJ, LevineM (1993) Binding affinities and cooperative interactions with bHLH activators delimit threshold responses to the dorsal gradient morphogen. Cell 72: 741–752.

86. RamosAI, BaroloS (2013) Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution. Philos Trans R Soc Lond B Biol Sci 368: 20130018.

87. ParkerDS, WhiteMA, RamosAI, CohenBA, BaroloS (2011) The cis-regulatory logic of Hedgehog gradient responses: key roles for gli binding affinity, competition, and cooperativity. Sci Signal 4: ra38.

88. WhiteMA, ParkerDS, BaroloS, CohenBA (2012) A model of spatially restricted transcription in opposing gradients of activators and repressors. Mol Syst Biol 8: 614.

89. JohnsonRA, InceTA, ScottoKW (2001) Transcriptional repression by p53 through direct binding to a novel DNA element. J Biol Chem 276: 27716–27720.

90. SurjitM, GantiKP, MukherjiA, YeT, HuaG, et al. (2011) Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell 145: 224–241.

91. BadisG, BergerMF, PhilippakisAA, TalukderS, GehrkeAR, et al. (2009) Diversity and complexity in DNA recognition by transcription factors. Science 324: 1720–1723.

92. HallikasO, TaipaleJ (2006) High-throughput assay for determining specificity and affinity of protein-DNA binding interactions. Nat Protoc 1: 215–222.

93. MaloofJN, WhangboJ, HarrisJM, JongewardGD, KenyonC (1999) A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans. Development 126: 37–49.

94. JiN, MiddelkoopTC, MentinkRA, BetistMC, TonegawaS, et al. (2013) Feedback Control of Gene Expression Variability in the Caenorhabditis elegans Wnt Pathway. Cell 155: 869–880.

95. MullerB, HartmannB, PyrowolakisG, AffolterM, BaslerK (2003) Conversion of an extracellular Dpp/BMP morphogen gradient into an inverse transcriptional gradient. Cell 113: 221–233.

96. HarmstonN, LenhardB (2013) Chromatin and epigenetic features of long-range gene regulation. Nucleic Acids Res 41: 7185–7199.

97. KwonD, MucciD, LanglaisKK, AmericoJL, DeVidoSK, et al. (2009) Enhancer-promoter communication at the Drosophila engrailed locus. Development 136: 3067–3075.

98. ZhangY, WongCH, BirnbaumRY, LiG, FavaroR, et al. (2013) Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature 504: 306–310.

99. LetticeLA, HeaneySJ, PurdieLA, LiL, de BeerP, et al. (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 12: 1725–1735.

100. Di CaraF, King-JonesK (2013) How clocks and hormones act in concert to control the timing of insect development. Curr Top Dev Biol 105: 1–36.

101. RewitzKF, YamanakaN, O'ConnorMB (2013) Developmental checkpoints and feedback circuits time insect maturation. Curr Top Dev Biol 103: 1–33.

102. DietzlG, ChenD, SchnorrerF, SuKC, BarinovaY, et al. (2007) A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448: 151–156.

103. SiegmundT, KorgeG (2001) Innervation of the ring gland of Drosophila melanogaster. J Comp Neurol 431: 481–491.

104. CadiganKM, NusseR (1996) wingless signaling in the Drosophila eye and embryonic epidermis. Development 122: 2801–2812.

105. Wilk R MurthySUM, YanH, KrauseHM (2010) In Situ Hybridization: Fruit Fly Embryos and Tissues. Current Protocols Essential Lab Techniques 4: 9.3.1–9.3.24.