Integrative Genomics to Dissect Retinoid Functions

  • Marco-Antonio Mendoza-Parra
  • Hinrich GronemeyerEmail author
Part of the Subcellular Biochemistry book series (SCBI, volume 70)


Retinoids and rexinoids, as all other ligands of the nuclear receptor (NR) family, act as ligand-regulated trans-acting transcription factors that bind to cis-acting DNA regulatory elements in the promoter regions of target genes (for reviews see [12, 22, 23, 26, 36]). Ligand binding modulates the communication functions of the receptor with the intracellular environment, which essentially entails receptor-protein and receptor-DNA or receptor-chromatin interactions. In this communication network, the receptor simultaneously serves as both intracellular sensor and regulator of cell/organ functions. Receptors are “intelligent” mediators of the information encoded in the chemical structure of a nuclear receptor ligand, as they interpret this information in the context of cellular identity and cell-physiological status and convert it into a dynamic chain of receptor-protein and receptor-DNA interactions. To process input and output information, they are composed of a modular structure with several domains that have evolved to exert particular molecular recognition functions. As detailed in other chapters in this volume, the main functional domains are the DNA-binding (DBD) and ligand-binding (LBD) [5, 6, 7, 38, 56, 71]. The LBD serves as a dual input-output information processor. Inputs, such as ligand binding or receptor phosphorylations, induce allosteric changes in receptor surfaces that serve as docking sites for outputs, such as subunits of transcription and epigenetic machineries or enzyme complexes. The complexity of input and output signals and their interdependencies is far from being understood.


Retinoic Acid Retinoic Acid Receptor Massive Parallel Sequencing Retinoic Acid Signaling Cell Fate Transition 
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.


9-cis RA

9-cis retinoid acid


RARα-selective synthetic ligand


Non-liganded NR


All-trans retinoic acid


RARα-selective synthetic ligand


RARγ-selective synthetic ligand


RARγ-selective synthetic ligand


The total set of genes in a given cell that contains cis-acting DNA binding/response/target sites for a given TF; generally defined by ChIP-seq and related technologies


Chromatin immunoprecipitation


ChIP coupled to massive parallel sequencing






DNA-binding domain


Embryo carcinoma cell (e.g., F9 or P19)


Embryonic stem cells


General term to describe the patterns of post-translational modification of chromatin histones alone the genome and the modification of DNA, such as methylation or hydroxymethylation of cytosines


Histone deacetylase






Three RAR and RXR receptors expressed from distinct genes (RARα, RARβ RARγ; RXRα, RXRβ and RXRγ)


Ligand-binding domain


Mouse embryonic fibroblast


Nuclear receptor

RAR α, β, γ

Retinoic acid receptor α, β, γ

RXR α, β, γ

Retinoid X receptor α, β, γ


Transcription factor


All transcribed RNAs produced in one or a population of cells.


  1. 1.
    Amat R, Gudas LJ (2010) RARgamma is required for correct deposition and removal of Suz12 and H2A.Z in embryonic stem cells. J Cell Physiol 226:293–298CrossRefGoogle Scholar
  2. 2.
    Arima K, Shiotsugu J, Niu R, Khandpur R, Martinez M, Shin Y, Koide T, Cho KW, Kitayama A, Ueno N et al (2005) Global analysis of RAR-responsive genes in the Xenopus neurula using cDNA microarrays. Dev Dyn 232:414–431PubMedCrossRefGoogle Scholar
  3. 3.
    Ashburner M, Chihara C, Meltzer P, Richards G (1974) Temporal control of puffing activity in polytene chromosomes. Cold Spring Harb Symp Quant Biol 38:655–662PubMedCrossRefGoogle Scholar
  4. 4.
    Balmer JE, Blomhoff R (2002) Gene expression regulation by retinoic acid. J Lipid Res 43:1773–1808PubMedCrossRefGoogle Scholar
  5. 5.
    Bourguet W, Germain P, Gronemeyer H (2000) Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. Trends Pharmacol Sci 21:381–388PubMedCrossRefGoogle Scholar
  6. 6.
    Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D (1995) Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α. Nature 375:377–382PubMedCrossRefGoogle Scholar
  7. 7.
    Bourguet W, Vivat V, Wurtz JM, Chambon P, Gronemeyer H, Moras D (2000) Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell 5:289–298PubMedCrossRefGoogle Scholar
  8. 8.
    Chaya D, Hayamizu T, Bustin M, Zaret KS (2001) Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in liver chromatin. J Biol Chem 276:44385–44389PubMedCrossRefGoogle Scholar
  9. 9.
    Chen W, Roeder RG (2011) Mediator-dependent nuclear receptor function. Semin Cell Dev Biol 22:749–758PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Chiba H, Clifford J, Metzger D, Chambon P (1997) Distinct retinoid X receptor-retinoic acid receptor heterodimers are differentially involved in the control of expression of retinoid target genes in F9 embryonal carcinoma cells. Mol Cell Biol 17:3013–3020PubMedCentralPubMedGoogle Scholar
  11. 11.
    Chiba H, Clifford J, Metzger D, Chambon P (1997) Specific and redundant functions of retinoid X Receptor/Retinoic acid receptor heterodimers in differentiation, proliferation, and apoptosis of F9 embryonal carcinoma cells. J Cell Biol 139:735–747PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    de Lera AR, Bourguet W, Altucci L, Gronemeyer H (2007) Design of selective nuclear receptor modulators: RAR and RXR as a case study. Nat Rev Drug Discov 6:811–820PubMedCrossRefGoogle Scholar
  13. 13.
    Delacroix L, Moutier E, Altobelli G, Legras S, Poch O, Choukrallah MA, Bertin I, Jost B, Davidson I (2010) Cell-specific interaction of retinoic acid receptors with target genes in mouse embryonic fibroblasts and embryonic stem cells. Mol Cell Biol 30:231–244PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Dimitrakopoulou K, Tsimpouris C, Papadopoulos G, Pommerenke C, Wilk E, Sgarbas KN, Schughart K, Bezerianos A (2011) Dynamic gene network reconstruction from gene expression data in mice after influenza A (H1N1) infection. J Clin Bioinform 1:27CrossRefGoogle Scholar
  15. 15.
    Dostie J, Richmond TA, Arnaout RA, Selzer RR, Lee WL, Honan TA, Rubio ED, Krumm A, Lamb J, Nusbaum C et al (2006) Chromosome conformation capture carbon copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res 16:1299–1309PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Eifert C, Sangster-Guity N, Yu LM, Chittur SV, Perez AV, Tine JA, McCormick PJ (2006) Global gene expression profiles associated with retinoic acid-induced differentiation of embryonal carcinoma cells. Mol Reprod Dev 73:796–824PubMedCrossRefGoogle Scholar
  17. 17.
    Ernst J, Kellis M (2010) Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotech 28:817–825CrossRefGoogle Scholar
  18. 18.
    Ernst J, Vainas O, Harbison CT, Simon I, Bar-Joseph Z (2007) Reconstructing dynamic regulatory maps. Mol Syst Biol 3:74PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Fadloun A, Kobi D, Delacroix L, Dembele D, Michel I, Lardenois A, Tisserand J, Losson R, Mengus G, Davidson I (2008) Retinoic acid induces TGFbeta-dependent autocrine fibroblast growth. Oncogene 27:477–489PubMedCrossRefGoogle Scholar
  20. 20.
    Felsenfeld G, Dekker J (2012) Genome architecture and expression. Curr Opin Genet Dev 22:59–61PubMedCrossRefGoogle Scholar
  21. 21.
    Fullwood MJ, Liu MH, Pan YF, Liu J, Xu H, Mohamed YB, Orlov YL, Velkov S, Ho A, Mei PH et al (2009) An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462:58–64PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev 58:712–725PubMedCrossRefGoogle Scholar
  23. 23.
    Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58:760–772PubMedCrossRefGoogle Scholar
  24. 24.
    Germain P, Iyer J, Zechel C, Gronemeyer H (2002) Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature 415:187–192PubMedCrossRefGoogle Scholar
  25. 25.
    Gillespie RF, Gudas LJ (2007) Retinoid regulated association of transcriptional co-regulators and the polycomb group protein SUZ12 with the retinoic acid response elements of Hoxa1, RARbeta(2), and Cyp26A1 in F9 embryonal carcinoma cells. J Mol Biol 372:298–316PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3:950–964PubMedCrossRefGoogle Scholar
  27. 27.
    Halbritter F, Vaidya HJ, Tomlinson SR (2012) GeneProf: analysis of high-throughput sequencing experiments. Nat Methods 9:7–8CrossRefGoogle Scholar
  28. 28.
    Handoko L, Xu H, Li G, Ngan CY, Chew E, Schnapp M, Lee CW, Ye C, Ping JL, Mulawadi F et al (2011) CTCF-mediated functional chromatin interactome in pluripotent cells. Nat Genet 43:630–638PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Harris TM, Childs G (2002) Global gene expression patterns during differentiation of F9 embryonal carcinoma cells into parietal endoderm. Funct Integr Genomics 2:105–119PubMedCrossRefGoogle Scholar
  30. 30.
    Hua S, Kittler R, White KP (2009) Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell 137:1259–1271PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Jin F, Li Y, Dixon JR, Selvaraj S, Ye Z, Lee AY, Yen CA, Schmitt AD, Espinoza CA, Ren B (2013) A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503:290–294PubMedGoogle Scholar
  32. 32.
    Kalhor R, Tjong H, Jayathilaka N, Alber F, Chen L (2012) Genome architectures revealed by tethered chromosome conformation capture and population-based modeling. Nat Biotechnol 30:90–98CrossRefGoogle Scholar
  33. 33.
    Kashyap V, Gudas LJ (2010) Epigenetic regulatory mechanisms distinguish retinoic acid-mediated transcriptional responses in stem cells and fibroblasts. J Biol Chem 285:14534–14548PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Kashyap V, Gudas LJ, Brenet F, Funk P, Viale A, Scandura JM (2011) Epigenomic reorganization of the clustered Hox genes in embryonic stem cells induced by retinoic acid. J Biol Chem 286:3250–3260PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Lalevee S, Anno YN, Chatagnon A, Samarut E, Poch O, Laudet V, Benoit G, Lecompte O, Rochette-Egly C (2011) Genome-wide in silico identification of new conserved and functional retinoic acid receptor response elements (direct repeats separated by 5 bp). J Biol Chem 286:33322–33334PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Laudet V, Gronemeyer H (2002) The nuclear receptor facts book. Academic Press, San DiegoGoogle Scholar
  37. 37.
    Laursen KB, Wong PM, Gudas LJ (2012) Epigenetic regulation by RARalpha maintains ligand-independent transcriptional activity. Nucleic Acids Res 40:102–115PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    le Maire A, Teyssier C, Erb C, Grimaldi M, Alvarez S, de Lera AR, Balaguer P, Gronemeyer H, Royer CA, Germain P, Bourguet W (2010) A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor. Nat Struct Mol Biol 17:801–807PubMedCrossRefGoogle Scholar
  39. 39.
    Li G, Fullwood MJ, Xu H, Mulawadi FH, Velkov S, Vega V, Ariyaratne PN, Mohamed YB, Ooi HS, Tennakoon C et al (2010) ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing. Genome Biol 11:R22PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Lyons P (2003) Advances in spotted microarray resources for expression profiling. Brief Funct Genomic Proteomic 2:21–30PubMedCrossRefGoogle Scholar
  41. 41.
    Mahony S, Mazzoni EO, McCuine S, Young RA, Wichterle H, Gifford DK (2011) Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biol 12:R2PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Mamoon A, Ventura-Holman T, Maher JF, Subauste JS (2008) Retinoic acid responsive genes in the murine hepatocyte cell line AML 12. Gene 408:95–103PubMedCrossRefGoogle Scholar
  43. 43.
    Meijsing SH, Pufall MA, So AY, Bates DL, Chen L, Yamamoto KR (2009) DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324:407–410PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Mendoza-Parra MA, Gronemeyer H (2013) Genome-wide studies of nuclear receptors in cell fate decisions. Semin Cell Dev Biol 24:706–715PubMedCrossRefGoogle Scholar
  45. 45.
    Mendoza-Parra MA, Nowicka M, Van Gool W, Gronemeyer H (2013) Characterising ChIP-seq binding patterns by model-based peak shape deconvolution. BMC Genom 14:834CrossRefGoogle Scholar
  46. 46.
    Mendoza-Parra MA, Shankaranarayanan P, Hinrich G (2012) Sequential chromatin immunoprecipitation protocol for global analysis through massive parallel sequencing (reChIP-seq)Google Scholar
  47. 47.
    Mendoza-Parra MA, Van Gool W, Mohamed Saleem MA, Ceschin DG, Gronemeyer H (2013) A quality control system for profiles obtained by ChIP sequencing. Nucleic Acids Res 41:e196PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Mendoza-Parra MA, Walia M, Sankar M, Gronemeyer H (2011) Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics. Mol Syst Biol 7:538PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Metivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M, Gannon F (2003) Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115:751–763PubMedCrossRefGoogle Scholar
  50. 50.
    Min IM, Pietramaggiori G, Kim FS, Passegue E, Stevenson KE, Wagers AJ (2008) The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell 2:380–391PubMedCrossRefGoogle Scholar
  51. 51.
    Nagano T, Lubling Y, Stevens TJ, Schoenfelder S, Yaffe E, Dean W, Laue ED, Tanay A, Fraser P (2013) Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 502:59–64PubMedCrossRefGoogle Scholar
  52. 52.
    Orkin SH, Wang J, Kim J, Chu J, Rao S, Theunissen TW, Shen X, Levasseur DN (2008) The transcriptional network controlling pluripotency in ES cells. Cold Spring Harb Symp Quant BiolGoogle Scholar
  53. 53.
    Perissi V, Jepsen K, Glass CK, Rosenfeld MG (2010) Deconstructing repression: evolving models of co-repressor action. Nat Rev Genet 11:109–123PubMedCrossRefGoogle Scholar
  54. 54.
    Rastinejad F, Perlmann T, Evans RM, Sigler PB (1995) Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature 375:203–211PubMedCrossRefGoogle Scholar
  55. 55.
    Rickman DS, Soong TD, Moss B, Mosquera JM, Dlabal J, Terry S, MacDonald TY, Tripodi J, Bunting K, Najfeld V et al (2012) Oncogene-mediated alterations in chromatin conformation. Proc Nat Acad Sci USA 109:9083–9088PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Rochel N, Ciesielski F, Godet J, Moman E, Roessle M, Peluso-Iltis C, Moulin M, Haertlein M, Callow P, Mely Y et al (2011) Common architecture of nuclear receptor heterodimers on DNA direct repeat elements with different spacings. Nat Struct Mol Biol 18:564–570PubMedCrossRefGoogle Scholar
  57. 57.
    Ross-Innes CS, Stark R, Holmes KA, Schmidt D, Spyrou C, Russell R, Massie CE, Vowler SL, Eldridge M, Carroll JS (2010) Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer. Genes Dev 24:171–182PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Schuster-Bockler B, Lehner B (2012) Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488:504–507PubMedCrossRefGoogle Scholar
  59. 59.
    Segraves WA, Hogness DS (1990) The E75 ecdysone-inducible gene responsible for the 75B early puff in Drosophila encodes two new members of the steroid receptor superfamily. Genes Dev 4:204–219PubMedCrossRefGoogle Scholar
  60. 60.
    Shankaranarayanan P, Mendoza-Parra MA, van Gool W, Trindade LM, Gronemeyer H (2012) Single-tube linear DNA amplification for genome-wide studies using a few thousand cells. Nat Protoc 7:328–338PubMedCrossRefGoogle Scholar
  61. 61.
    Shankaranarayanan P, Mendoza-Parra MA, Walia M, Wang L, Li N, Trindade LM, Gronemeyer H (2011) Single-tube linear DNA amplification (LinDA) for robust ChIP-seq. Nat Meth 8:565–567CrossRefGoogle Scholar
  62. 62.
    Soler E, Andrieu-Soler C, de Boer E, Bryne JC, Thongjuea S, Stadhouders R, Palstra RJ, Stevens M, Kockx C, van Ijcken W et al (2010) The genome-wide dynamics of the binding of Ldb1 complexes during erythroid differentiation. Genes Dev 24:277–289PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Su D, Gudas LJ (2008) Gene expression profiling elucidates a specific role for RARgamma in the retinoic acid-induced differentiation of F9 teratocarcinoma stem cells. Biochem Pharmacol 75:1129–1160PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Sutherland H, Bickmore WA (2009) Transcription factories: gene expression in unions? Nat Rev Genet 10:457–466PubMedCrossRefGoogle Scholar
  65. 65.
    Taneja R, Roy B, Plassat JL, Zusi CF, Ostrowski J, Reczek PR, Chambon P (1996) Cell-type and promoter-context dependent retinoic acid receptor (RAR) redundancies for RAR beta 2 and Hoxa-1 activation in F9 and P19 cells can be artefactually generated by gene knockouts. Proc Nat Acad Sci USA 93:6197–6202PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Thummel CS (2001) Molecular mechanisms of developmental timing in C. elegans and Drosophila. Dev Cell 1:453–465PubMedCrossRefGoogle Scholar
  67. 67.
    Umesono K, Murakami KK, Thompson CC, Evans RM (1991) Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 65:1255–1266PubMedCrossRefGoogle Scholar
  68. 68.
    van Berkum NL, Lieberman-Aiden E, Williams L, Imakaev M, Gnirke A, Mirny LA, Dekker J, Lander ES (2010) Hi-C: a method to study the three-dimensional architecture of genomes. J Vis ExpGoogle Scholar
  69. 69.
    Voss TC, Schiltz RL, Sung MH, Yen PM, Stamatoyannopoulos JA, Biddie SC, Johnson TA, Miranda TB, John S, Hager GL (2011) Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell 146:544–554PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Wei Y, Harris T, Childs G (2002) Global gene expression patterns during neural differentiation of P19 embryonic carcinoma cells. Differentiation 70:204–219PubMedCrossRefGoogle Scholar
  71. 71.
    Wurtz JM, Bourguet W, Renaud JP, Vivat V, Chambon P, Moras D, Gronemeyer H (1996) A canonical structure for the ligand-binding domain of nuclear receptors. Nat Struct Biol 3:206PubMedCrossRefGoogle Scholar
  72. 72.
    Yao TP, Segraves WA, Oro AE, McKeown M, Evans RM (1992) Drosophila ultraspiracle modulates ecdysone receptor function via heterodimer formation. Cell 71:63–72PubMedCrossRefGoogle Scholar
  73. 73.
    Zaret KS, Carroll JS (2011) Pioneer transcription factors: establishing competence for gene expression. Genes Dev 25:2227–2241PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Zechel C, Shen XQ, Chambon P, Gronemeyer H (1994) Dimerization interfaces formed between the DNA binding domains determine the cooperative binding of RXR/RAR and RXR/TR heterodimers to DR5 and DR4 elements. EMBO J 13:1414–1424PubMedCentralPubMedGoogle Scholar
  75. 75.
    Zechel C, Shen XQ, Chen JY, Chen ZP, Chambon P, Gronemeyer H (1994) The dimerization interfaces formed between the DNA binding domains of RXR, RAR and TR determine the binding specificity and polarity of the full-length receptors to direct repeats. EMBO J 13:1425–1433PubMedCentralPubMedGoogle Scholar
  76. 76.
    Zhang J, Chalmers MJ, Stayrook KR, Burris LL, Wang Y, Busby SA, Pascal BD, Garcia-Ordonez RD, Bruning JB, Istrate MA et al (2011) DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex. Nat Struct Mol Biol 18:556–563PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Zhao Z, Tavoosidana G, Sjolinder M, Gondor A, Mariano P, Wang S, Kanduri C, Lezcano M, Sandhu KS, Singh U et al (2006) Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nat Genet 38:1341–1347PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Marco-Antonio Mendoza-Parra
    • 1
  • Hinrich Gronemeyer
    • 1
    Email author
  1. 1.Department of Functional Genomics and CancerInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS, INSERM, Université de StrasbourgIllkirch CedexFrance

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