IKAROS is required for the measured response of NOTCH target genes upon external NOTCH signaling

Autoři: Maud Lemarié aff001;  Stefania Bottardi aff001;  Lionel Mavoungou aff001;  Helen Pak aff001;  Eric Milot aff001
Působiště autorů: Maisonneuve-Rosemont Hospital Research Center; CIUSSS de l’est de l’Île de Montréal, Montréal, QC, Canada aff001;  Department of Medicine, Université de Montréal, Montréal, Québec, Canada aff002
Vyšlo v časopise: IKAROS is required for the measured response of NOTCH target genes upon external NOTCH signaling. PLoS Genet 17(3): e1009478. doi:10.1371/journal.pgen.1009478
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009478


The tumor suppressor IKAROS binds and represses multiple NOTCH target genes. For their induction upon NOTCH signaling, IKAROS is removed and replaced by NOTCH Intracellular Domain (NICD)-associated proteins. However, IKAROS remains associated to other NOTCH activated genes upon signaling and induction. Whether IKAROS could participate to the induction of this second group of NOTCH activated genes is unknown. We analyzed the combined effect of IKAROS abrogation and NOTCH signaling on the expression of NOTCH activated genes in erythroid cells. In IKAROS-deleted cells, we observed that many of these genes were either overexpressed or no longer responsive to NOTCH signaling. IKAROS is then required for the organization of bivalent chromatin and poised transcription of NOTCH activated genes belonging to either of the aforementioned groups. Furthermore, we show that IKAROS-dependent poised organization of the NOTCH target Cdkn1a is also required for its adequate induction upon genotoxic insults. These results highlight the critical role played by IKAROS in establishing bivalent chromatin and transcriptional poised state at target genes for their activation by NOTCH or other stress signals.

Klíčová slova:

DNA transcription – Gene expression – Gene regulation – Chromatin – Chromatin immunoprecipitation – Immunoprecipitation – Notch signaling – Tumor suppressor genes


1. de Bruijn M. Turning it down a Notch. Blood. 2016;128(12):1541–2. Epub 2016/09/24. doi: 10.1182/blood-2016-08-729483 27658698.

2. Pajcini KV, Speck NA, Pear WS. Notch signaling in mammalian hematopoietic stem cells. Leukemia. 2011;25(10):1525–32. Epub 2011/06/08. doi: 10.1038/leu.2011.127 21647159; PubMed Central PMCID: PMC5924479.

3. Jeannet R, Mastio J, Macias-Garcia A, Oravecz A, Ashworth T, Geimer Le Lay AS, et al. Oncogenic activation of the Notch1 gene by deletion of its promoter in Ikaros-deficient T-ALL. Blood. 2010;116(25):5443–54. Epub 2010/09/11. doi: 10.1182/blood-2010-05-286658 20829372; PubMed Central PMCID: PMC3100247.

4. Weng AP, Ferrando AA, Lee W, Morris JPt, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–71. Epub 2004/10/09. doi: 10.1126/science.1102160 15472075.

5. Oswald F, Tauber B, Dobner T, Bourteele S, Kostezka U, Adler G, et al. p300 acts as a transcriptional coactivator for mammalian Notch-1. Mol Cell Biol. 2001;21(22):7761–74. Epub 2001/10/18. doi: 10.1128/MCB.21.22.7761-7774.2001 11604511; PubMed Central PMCID: PMC99946.

6. Krejci A, Bray S. Notch activation stimulates transient and selective binding of Su(H)/CSL to target enhancers. Genes Dev. 2007;21(11):1322–7. Epub 2007/06/05. doi: 10.1101/gad.424607 17545467; PubMed Central PMCID: PMC1877745.

7. Geimer Le Lay AS, Oravecz A, Mastio J, Jung C, Marchal P, Ebel C, et al. The tumor suppressor Ikaros shapes the repertoire of notch target genes in T cells. Sci Signal. 2014;7(317):ra28. Epub 2014/03/20. doi: 10.1126/scisignal.2004545 24643801.

8. Yatim A, Benne C, Sobhian B, Laurent-Chabalier S, Deas O, Judde JG, et al. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol Cell. 2012;48(3):445–58. Epub 2012/10/02. doi: 10.1016/j.molcel.2012.08.022 23022380; PubMed Central PMCID: PMC3595990.

9. Chari S, Winandy S. Ikaros regulates Notch target gene expression in developing thymocytes. J Immunol. 2008;181(9):6265–74. Epub 2008/10/23. 181/9/6265 [pii]. doi: 10.4049/jimmunol.181.9.6265 18941217.

10. Kathrein KL, Chari S, Winandy S. Ikaros directly represses the notch target gene Hes1 in a leukemia T cell line: implications for CD4 regulation. J Biol Chem. 2008;283(16):10476–84. Epub 2008/02/22. M709643200 [pii] doi: 10.1074/jbc.M709643200 18287091.

11. Kleinmann E, Geimer Le Lay AS, Sellars M, Kastner P, Chan S. Ikaros represses the transcriptional response to Notch signaling in T-cell development. Mol Cell Biol. 2008;28(24):7465–75. Epub 2008/10/15. MCB.00715-08 [pii] doi: 10.1128/MCB.00715-08 18852286.

12. Malinge S, Thiollier C, Chlon TM, Dore LC, Diebold L, Bluteau O, et al. Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling. Blood. 2013. doi: 10.1182/blood-2012-08-450627 23335373.

13. Ross J, Mavoungou L, Bresnick EH, Milot E. GATA-1 utilizes Ikaros and polycomb repressive complex 2 to suppress Hes1 and to promote erythropoiesis. Mol Cell Biol. 2012;32(18):3624–38. doi: 10.1128/MCB.00163-12 22778136; PubMed Central PMCID: PMC3430200.

14. Oravecz A, Apostolov A, Polak K, Jost B, Le Gras S, Chan S, et al. Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2. Nat Commun. 2015;6:8823. Epub 2015/11/10. doi: 10.1038/ncomms9823 26549758; PubMed Central PMCID: PMC4667618.

15. Bellavia D, Mecarozzi M, Campese AF, Grazioli P, Gulino A, Screpanti I. Notch and Ikaros: not only converging players in T cell leukemia. Cell Cycle. 2007;6(22):2730–4. Epub 2007/11/23. 4894 [pii]. doi: 10.4161/cc.6.22.4894 18032925.

16. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678–89. Epub 2006/08/22. nrm2009 [pii] doi: 10.1038/nrm2009 16921404.

17. Bottardi S, Mavoungou L, Milot E. IKAROS: a multifunctional regulator of the polymerase II transcription cycle. Trends Genet. 2015;31(9):500–8. Epub 2015/06/08. doi: 10.1016/j.tig.2015.05.003 26049627.

18. Bottardi S, Zmiri FA, Bourgoin V, Ross J, Mavoungou L, Milot E. Ikaros interacts with P-TEFb and cooperates with GATA-1 to enhance transcription elongation. Nucleic Acids Res. 2011;39(9):3505–19. Epub 2011/01/20. gkq1271 [pii] 10.1093/nar/gkq1271. doi: 10.1093/nar/gkq1271 21245044; PubMed Central PMCID: PMC3089448.

19. Georgopoulos K. Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nat Rev Immunol. 2002;2(3):162–74. doi: 10.1038/nri747 11913067.

20. Rodriguez P, Bonte E, Krijgsveld J, Kolodziej KE, Guyot B, Heck AJ, et al. GATA-1 forms distinct activating and repressive complexes in erythroid cells. Embo J. 2005;24(13):2354–66. doi: 10.1038/sj.emboj.7600702 15920471.

21. Brown KE, Guest SS, Smale ST, Hahm K, Merkenschlager M, Fisher AG. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell. 1997;91(6):845–54. doi: 10.1016/s0092-8674(00)80472-9 9413993.

22. Zhang J, Jackson AF, Naito T, Dose M, Seavitt J, Liu F, et al. Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis. Nat Immunol. 2011;13(1):86–94. Epub 2011/11/15. doi: 10.1038/ni.2150 22080921; PubMed Central PMCID: PMC3868219.

23. Bottardi S, Mavoungou L, Pak H, Daou S, Bourgoin V, Lakehal YA, et al. The IKAROS interaction with a complex including chromatin remodeling and transcription elongation activities is required for hematopoiesis. PLoS Genet. 2014;10(12):e1004827. Epub 2014/12/05. doi: 10.1371/journal.pgen.1004827 25474253; PubMed Central PMCID: PMC4256266.

24. Miccio A, Wang Y, Hong W, Gregory GD, Wang H, Yu X, et al. NuRD mediates activating and repressive functions of GATA-1 and FOG-1 during blood development. EMBO J. 2010;29(2):442–56. Epub 2009/11/21. doi: 10.1038/emboj.2009.336 19927129; PubMed Central PMCID: PMC2824460.

25. Yoshida T, Hazan I, Zhang J, Ng SY, Naito T, Snippert HJ, et al. The role of the chromatin remodeler Mi-2beta in hematopoietic stem cell self-renewal and multilineage differentiation. Genes Dev. 2008;22(9):1174–89. Epub 2008/05/03. doi: 10.1101/gad.1642808 18451107; PubMed Central PMCID: PMC2335314.

26. Wada T, Takagi T, Yamaguchi Y, Watanabe D, Handa H. Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J. 1998;17(24):7395–403. Epub 1998/12/19. doi: 10.1093/emboj/17.24.7395 9857195; PubMed Central PMCID: PMC1171084.

27. Peterlin BM, Price DH. Controlling the elongation phase of transcription with P-TEFb. Mol Cell. 2006;23(3):297–305. Epub 2006/08/04. doi: 10.1016/j.molcel.2006.06.014 16885020.

28. Popescu M, Gurel Z, Ronni T, Song C, Hung KY, Payne KJ, et al. Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1. J Biol Chem. 2009;284(20):13869–80. Epub 2009/03/14. M900209200 [pii] doi: 10.1074/jbc.M900209200 19282287.

29. Bottardi S, Ross J, Bourgoin V, Fotouhi-Ardakani N, Affar el B, Trudel M, et al. Ikaros and GATA-1 combinatorial effect is required for silencing of human gamma-globin genes. Mol Cell Biol. 2009;29(6):1526–37. Epub 2008/12/31. MCB.01523-08 [pii] doi: 10.1128/MCB.01523-08 19114560.

30. Wang JH, Nichogiannopoulou A, Wu L, Sun L, Sharpe AH, Bigby M, et al. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity. 1996;5(6):537–49. doi: 10.1016/s1074-7613(00)80269-1 8986714.

31. Winandy S, Wu P, Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995;83(2):289–99. doi: 10.1016/0092-8674(95)90170-1 7585946.

32. Dumortier A, Kirstetter P, Kastner P, Chan S. Ikaros regulates neutrophil differentiation. Blood. 2003;101(6):2219–26. doi: 10.1182/blood-2002-05-1336 12406904.

33. Ferreiros-Vidal I, Carroll T, Taylor B, Terry A, Liang Z, Bruno L, et al. Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation. Blood. 2013;121(10):1769–82. Epub 2013/01/11. doi: 10.1182/blood-2012-08-450114 23303821.

34. Francis OL, Payne JL, Su RJ, Payne KJ. Regulator of myeloid differentiation and function: The secret life of Ikaros. World J Biol Chem. 2011;2(6):119–25. Epub 2011/07/19. doi: 10.4331/wjbc.v2.i6.119 21765977; PubMed Central PMCID: PMC3135858.

35. Georgopoulos K, Moore DD, Derfler B. Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science. 1992;258(5083):808–12. doi: 10.1126/science.1439790 1439790.

36. Schwickert TA, Tagoh H, Gultekin S, Dakic A, Axelsson E, Minnich M, et al. Stage-specific control of early B cell development by the transcription factor Ikaros. Nat Immunol. 2014;15(3):283–93. Epub 2014/02/11. doi: 10.1038/ni.2828 24509509; PubMed Central PMCID: PMC5790181.

37. Yoshida T, Ng SY, Georgopoulos K. Awakening lineage potential by Ikaros-mediated transcriptional priming. Curr Opin Immunol. 2010;22(2):154–60. doi: 10.1016/j.coi.2010.02.011 20299195.

38. Sun L, Goodman PA, Wood CM, Crotty ML, Sensel M, Sather H, et al. Expression of aberrantly spliced oncogenic ikaros isoforms in childhood acute lymphoblastic leukemia. J Clin Oncol. 1999;17(12):3753–66. doi: 10.1200/JCO.1999.17.12.3753 10577847.

39. Bank A. Regulation of human fetal hemoglobin: new players, new complexities. Blood. 2006;107(2):435–43. doi: 10.1182/blood-2005-05-2113 16109777; PubMed Central PMCID: PMC1895603.

40. Keys JR, Tallack MR, Zhan Y, Papathanasiou P, Goodnow CC, Gaensler KM, et al. A mechanism for Ikaros regulation of human globin gene switching. Br J Haematol. 2008;141(3):398–406. Epub 2008/03/06. BJH7065 [pii] doi: 10.1111/j.1365-2141.2008.07065.x 18318763.

41. Nichogiannopoulou A, Trevisan M, Neben S, Friedrich C, Georgopoulos K. Defects in hemopoietic stem cell activity in Ikaros mutant mice. J Exp Med. 1999;190(9):1201–14. doi: 10.1084/jem.190.9.1201 10544193.

42. Lopez RA, Schoetz S, DeAngelis K, O’Neill D, Bank A. Multiple hematopoietic defects and delayed globin switching in Ikaros null mice. Proc Natl Acad Sci U S A. 2002;99(2):602–7. doi: 10.1073/pnas.022412699 11805317.

43. Schmitt TM, Zuniga-Pflucker JC. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity. 2002;17(6):749–56. Epub 2002/12/14. doi: 10.1016/s1074-7613(02)00474-0 12479821.

44. de Pooter R, Zuniga-Pflucker JC. T-cell potential and development in vitro: the OP9-DL1 approach. Curr Opin Immunol. 2007;19(2):163–8. doi: 10.1016/j.coi.2007.02.011 17303399.

45. Kutlesa S, Zayas J, Valle A, Levy RB, Jurecic R. T-cell differentiation of multipotent hematopoietic cell line EML in the OP9-DL1 coculture system. Exp Hematol. 2009;37(8):909–23. Epub 2009/05/19. doi: 10.1016/j.exphem.2009.05.002 19447159; PubMed Central PMCID: PMC3072798.

46. Kina T, Ikuta K, Takayama E, Wada K, Majumdar AS, Weissman IL, et al. The monoclonal antibody TER-119 recognizes a molecule associated with glycophorin A and specifically marks the late stages of murine erythroid lineage. Br J Haematol. 2000;109(2):280–7. Epub 2000/06/10. doi: 10.1046/j.1365-2141.2000.02037.x 10848813.

47. Anders S, Huber W. Differential expression analysis for sequence count data. Genome Biol. 2010;11(10):R106. Epub 2010/10/29. doi: 10.1186/gb-2010-11-10-r106 20979621; PubMed Central PMCID: PMC3218662.

48. Bigas A, Espinosa L. Hematopoietic stem cells: to be or Notch to be. Blood. 2012;119(14):3226–35. doi: 10.1182/blood-2011-10-355826 22308291.

49. Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros gene in lymphocyte development and homeostasis. Annu Rev Immunol. 1997;15:155–76. Epub 1997/01/01. doi: 10.1146/annurev.immunol.15.1.155 9143685.

50. Dumortier A, Jeannet R, Kirstetter P, Kleinmann E, Sellars M, dos Santos NR, et al. Notch activation is an early and critical event during T-Cell leukemogenesis in Ikaros-deficient mice. Mol Cell Biol. 2006;26(1):209–20. Epub 2005/12/16. 26/1/209 [pii] doi: 10.1128/MCB.26.1.209-220.2006 16354692.

51. Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57. Epub 2009/01/10. doi: 10.1038/nprot.2008.211 19131956.

52. Huang da W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37(1):1–13. Epub 2008/11/27. doi: 10.1093/nar/gkn923 19033363; PubMed Central PMCID: PMC2615629.

53. Brooks CL, Gu W. p53 regulation by ubiquitin. FEBS Lett. 2011;585(18):2803–9. Epub 2011/06/01. doi: 10.1016/j.febslet.2011.05.022 21624367; PubMed Central PMCID: PMC3172401.

54. Maclaine NJ, Hupp TR. The regulation of p53 by phosphorylation: a model for how distinct signals integrate into the p53 pathway. Aging (Albany NY). 2009;1(5):490–502. Epub 2010/02/17. doi: 10.18632/aging.100047 20157532; PubMed Central PMCID: PMC2806026.

55. Li Y, Hibbs MA, Gard AL, Shylo NA, Yun K. Genome-wide analysis of N1ICD/RBPJ targets in vivo reveals direct transcriptional regulation of Wnt, SHH, and hippo pathway effectors by Notch1. Stem Cells. 2012;30(4):741–52. Epub 2012/01/11. doi: 10.1002/stem.1030 22232070; PubMed Central PMCID: PMC3734558.

56. Liu H, Zhou P, Lan H, Chen J, Zhang YX. Comparative analysis of Notch1 and Notch2 binding sites in the genome of BxPC3 pancreatic cancer cells. J Cancer. 2017;8(1):65–73. Epub 2017/01/27. doi: 10.7150/jca.16739 28123599; PubMed Central PMCID: PMC5264041.

57. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 2001;20(13):3427–36. Epub 2001/07/04. doi: 10.1093/emboj/20.13.3427 11432830; PubMed Central PMCID: PMC125257.

58. Gorospe M, Wang X, Holbrook NJ. Functional role of p21 during the cellular response to stress. Gene Expr. 1999;7(4–6):377–85. Epub 1999/08/10. 10440238; PubMed Central PMCID: PMC6174658.

59. Karimian A, Ahmadi Y, Yousefi B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst). 2016;42:63–71. Epub 2016/05/09. doi: 10.1016/j.dnarep.2016.04.008 27156098.

60. Ng SY, Yoshida T, Zhang J, Georgopoulos K. Genome-wide lineage-specific transcriptional networks underscore Ikaros-dependent lymphoid priming in hematopoietic stem cells. Immunity. 2009;30(4):493–507. doi: 10.1016/j.immuni.2009.01.014 19345118; PubMed Central PMCID: PMC3012962.

61. Zhou Z, Li X, Deng C, Ney PA, Huang S, Bungert J. USF and NF-E2 cooperate to regulate the recruitment and activity of RNA polymerase II in the beta-globin gene locus. J Biol Chem. 285(21):15894–905. Epub 2010/03/20. M109.098376 [pii] doi: 10.1074/jbc.M109.098376 20236933.

62. Gates LA, Foulds CE, O’Malley BW. Histone Marks in the ’Driver’s Seat’: Functional Roles in Steering the Transcription Cycle. Trends Biochem Sci. 2017;42(12):977–89. Epub 2017/11/11. doi: 10.1016/j.tibs.2017.10.004 29122461; PubMed Central PMCID: PMC5701853.

63. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125(2):315–26. doi: 10.1016/j.cell.2006.02.041 16630819.

64. Voigt P, Tee WW, Reinberg D. A double take on bivalent promoters. Genes Dev. 2013;27(12):1318–38. Epub 2013/06/22. doi: 10.1101/gad.219626.113 23788621; PubMed Central PMCID: PMC3701188.

65. Deng C, Li Y, Liang S, Cui K, Salz T, Yang H, et al. USF1 and hSET1A mediated epigenetic modifications regulate lineage differentiation and HoxB4 transcription. PLoS Genet. 2013;9(6):e1003524. Epub 2013/06/12. doi: 10.1371/journal.pgen.1003524 23754954; PubMed Central PMCID: PMC3675019.

66. Rylski M, Welch JJ, Chen YY, Letting DL, Diehl JA, Chodosh LA, et al. GATA-1-mediated proliferation arrest during erythroid maturation. Mol Cell Biol. 2003;23(14):5031–42. Epub 2003/07/02. doi: 10.1128/mcb.23.14.5031-5042.2003 12832487.

67. Simon MC, Pevny L, Wiles MV, Keller G, Costantini F, Orkin SH. Rescue of erythroid development in gene targeted GATA-1- mouse embryonic stem cells. Nat Genet. 1992;1(2):92–8. Epub 1992/05/01. doi: 10.1038/ng0592-92 1302015.

68. Weiss MJ, Yu C, Orkin SH. Erythroid-cell-specific properties of transcription factor GATA-1 revealed by phenotypic rescue of a gene-targeted cell line. Mol Cell Biol. 1997;17(3):1642–51. Epub 1997/03/01. doi: 10.1128/mcb.17.3.1642 9032291.

69. Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M, Zhuo D, et al. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Mol Cell Biol. 2008;28(8):2825–39. Epub 2008/02/21. doi: 10.1128/MCB.02076-07 18285465; PubMed Central PMCID: PMC2293113.

70. Georgopoulos K. The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma. Genes Dev. 2017;31(5):439–50. Epub 2017/04/08. doi: 10.1101/gad.297002.117 28385788; PubMed Central PMCID: PMC5393059.

71. Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, et al. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity. 1999;10(3):345–55. doi: 10.1016/s1074-7613(00)80034-5 10204490.

72. O’Neill DW, Schoetz SS, Lopez RA, Castle M, Rabinowitz L, Shor E, et al. An ikaros-containing chromatin-remodeling complex in adult-type erythroid cells. Mol Cell Biol. 2000;20(20):7572–82. doi: 10.1128/mcb.20.20.7572-7582.2000 11003653.

73. Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, et al. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011;117(19):5057–66. Epub 2011/02/24. doi: 10.1182/blood-2010-08-300145 21343612; PubMed Central PMCID: PMC3109532.

74. Nishikata I, Sasaki H, Iga M, Tateno Y, Imayoshi S, Asou N, et al. A novel EVI1 gene family, MEL1, lacking a PR domain (MEL1S) is expressed mainly in t(1;3)(p36;q21)-positive AML and blocks G-CSF-induced myeloid differentiation. Blood. 2003;102(9):3323–32. Epub 2003/06/21. doi: 10.1182/blood-2002-12-3944 12816872.

75. Sakai I, Tamura T, Narumi H, Uchida N, Yakushijin Y, Hato T, et al. Novel RUNX1-PRDM16 fusion transcripts in a patient with acute myeloid leukemia showing t(1;21)(p36;q22). Genes Chromosomes Cancer. 2005;44(3):265–70. Epub 2005/07/15. doi: 10.1002/gcc.20241 16015645.

76. Corrigan DJ, Luchsinger LL, Justino de Almeida M, Williams LJ, Strikoudis A, Snoeck HW. PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature. J Clin Invest. 2018;128(8):3250–64. Epub 2018/06/08. doi: 10.1172/JCI99862 29878897; PubMed Central PMCID: PMC6063481.

77. Krebs LT, Deftos ML, Bevan MJ, Gridley T. The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway. Dev Biol. 2001;238(1):110–9. Epub 2002/01/11. doi: 10.1006/dbio.2001.0408 11783997.

78. Chu BF, Qin YY, Zhang SL, Quan ZW, Zhang MD, Bi JW. Downregulation of Notch-regulated Ankyrin Repeat Protein Exerts Antitumor Activities against Growth of Thyroid Cancer. Chin Med J (Engl). 2016;129(13):1544–52. Epub 2016/07/02. doi: 10.4103/0366-6999.184465 27364790; PubMed Central PMCID: PMC4931260.

79. Imaoka T, Okutani T, Daino K, Iizuka D, Nishimura M, Shimada Y. Overexpression of NOTCH-regulated ankyrin repeat protein is associated with breast cancer cell proliferation. Anticancer Res. 2014;34(5):2165–71. Epub 2014/04/30. 24778018.

80. Liao Y, Chen J, Ma J, Mao Q, Wei R, Zheng J. Notch-regulated ankyrin-repeat protein is a novel tissue biomarker that predicts poor prognosis in non-small cell lung cancer. Oncol Lett. 2018;16(2):1885–91. Epub 2018/07/17. doi: 10.3892/ol.2018.8826 30008880; PubMed Central PMCID: PMC6036336.

81. Zhu Y, Wang W, Wang X. Roles of transcriptional factor 7 in production of inflammatory factors for lung diseases. J Transl Med. 2015;13:273. Epub 2015/08/21. doi: 10.1186/s12967-015-0617-7 26289446; PubMed Central PMCID: PMC4543455.

82. Durinck K, Wallaert A, Van de Walle I, Van Loocke W, Volders PJ, Vanhauwaert S, et al. The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia. Haematologica. 2014;99(12):1808–16. Epub 2014/10/26. doi: 10.3324/haematol.2014.115683 25344525; PubMed Central PMCID: PMC4258754.

83. Fabbri G, Holmes AB, Viganotti M, Scuoppo C, Belver L, Herranz D, et al. Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2017;114(14):E2911–E9. Epub 2017/03/21. doi: 10.1073/pnas.1702564114 28314854; PubMed Central PMCID: PMC5389283.

84. Ashley RJ, Yan H, Wang N, Hale J, Dulmovits BM, Papoin J, et al. Steroid resistance in Diamond Blackfan anemia associates with p57Kip2 dysregulation in erythroid progenitors. J Clin Invest. 2020;130(4):2097–110. Epub 2020/01/22. doi: 10.1172/JCI132284 31961825; PubMed Central PMCID: PMC7108903.

85. Bottardi S, Aumont A, Grosveld F, Milot E. Developmental stage-specific epigenetic control of human beta-globin gene expression is potentiated in hematopoietic progenitor cells prior to their transcriptional activation. Blood. 2003;102(12):3989–97. doi: 10.1182/blood-2003-05-1540 12920025.

86. Bottardi S, Bourgoin V, Pierre-Charles N, Milot E. Onset and inheritance of abnormal epigenetic regulation in hematopoietic cells. Hum Mol Genet. 2005;14(4):493–502. doi: 10.1093/hmg/ddi046 15615768.

87. Bottardi S, Ross J, Pierre-Charles N, Blank V, Milot E. Lineage-specific activators affect beta-globin locus chromatin in multipotent hematopoietic progenitors. Embo J. 2006;25(15):3586–95. doi: 10.1038/sj.emboj.7601232 16858401.

88. Kontaraki J, Chen HH, Riggs A, Bonifer C. Chromatin fine structure profiles for a developmentally regulated gene: reorganization of the lysozyme locus before trans-activator binding and gene expression. Genes Dev. 2000;14(16):2106–22. 10950873.

89. Ludwig LS, Lareau CA, Bao EL, Nandakumar SK, Muus C, Ulirsch JC, et al. Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis. Cell Rep. 2019;27(11):3228–40 e7. Epub 2019/06/13. doi: 10.1016/j.celrep.2019.05.046 31189107; PubMed Central PMCID: PMC6579117.

90. Williams AB, Schumacher B. p53 in the DNA-Damage-Repair Process. Cold Spring Harb Perspect Med. 2016;6(5). Epub 2016/04/07. doi: 10.1101/cshperspect.a026070 27048304; PubMed Central PMCID: PMC4852800.

91. Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343(6168):301–5. Epub 2013/12/03. doi: 10.1126/science.1244851 24292625; PubMed Central PMCID: PMC4077049.

92. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343(6168):305–9. Epub 2013/12/03. doi: 10.1126/science.1244917 24292623; PubMed Central PMCID: PMC4070318.

93. Merz M, Dechow T, Scheytt M, Schmidt C, Hackanson B, Knop S. The clinical management of lenalidomide-based therapy in patients with newly diagnosed multiple myeloma. Ann Hematol. 2020;99(8):1709–25. Epub 2020/04/17. doi: 10.1007/s00277-020-04023-4 32296915; PubMed Central PMCID: PMC7340649.

94. Stahl M, Zeidan AM. Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications. Cancer. 2017;123(10):1703–13. Epub 2017/02/14. doi: 10.1002/cncr.30585 28192601.

95. Darracq A, Pak H, Bourgoin V, Zmiri F, Dellaire G, Affar EB, et al. NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes. PLoS Genet. 2019;15(11):e1008463. Epub 2019/11/02. doi: 10.1371/journal.pgen.1008463 31675375; PubMed Central PMCID: PMC6853375.

96. Hoffmeister H, Fuchs A, Erdel F, Pinz S, Grobner-Ferreira R, Bruckmann A, et al. CHD3 and CHD4 form distinct NuRD complexes with different yet overlapping functionality. Nucleic Acids Res. 2017;45(18):10534–54. Epub 2017/10/05. doi: 10.1093/nar/gkx711 28977666; PubMed Central PMCID: PMC5737555.

97. Bornelov S, Reynolds N, Xenophontos M, Gharbi S, Johnstone E, Floyd R, et al. The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression. Mol Cell. 2018;71(1):56–72 e4. Epub 2018/07/17. doi: 10.1016/j.molcel.2018.06.003 30008319; PubMed Central PMCID: PMC6039721.

98. Ho L, Miller EL, Ronan JL, Ho WQ, Jothi R, Crabtree GR. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nat Cell Biol. 2011;13(8):903–13. Epub 2011/07/26. doi: 10.1038/ncb2285 21785422; PubMed Central PMCID: PMC3155811.

99. King HW, Klose RJ. The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells. Elife. 2017;6. Epub 2017/03/14. doi: 10.7554/eLife.22631 28287392; PubMed Central PMCID: PMC5400504.

100. Bracken AP, Brien GL, Verrijzer CP. Dangerous liaisons: interplay between SWI/SNF, NuRD, and Polycomb in chromatin regulation and cancer. Genes Dev. 2019;33(15–16):936–59. Epub 2019/05/28. doi: 10.1101/gad.326066.119 31123059; PubMed Central PMCID: PMC6672049.

101. Mohd-Sarip A, Teeuwssen M, Bot AG, De Herdt MJ, Willems SM, Baatenburg de Jong RJ, et al. DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells. Cell Rep. 2017;20(1):61–75. Epub 2017/07/07. doi: 10.1016/j.celrep.2017.06.020 28683324.

102. Li Y, Schulz VP, Deng C, Li G, Shen Y, Tusi BK, et al. Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation. Nucleic Acids Res. 2016;44(15):7173–88. Epub 2016/05/05. doi: 10.1093/nar/gkw327 27141965; PubMed Central PMCID: PMC5009724.

103. Rother MB, van Attikum H. DNA repair goes hip-hop: SMARCA and CHD chromatin remodellers join the break dance. Philos Trans R Soc Lond B Biol Sci. 2017;372(1731). Epub 2017/08/30. doi: 10.1098/rstb.2016.0285 28847822; PubMed Central PMCID: PMC5577463.

104. Corey LL, Weirich CS, Benjamin IJ, Kingston RE. Localized recruitment of a chromatin-remodeling activity by an activator in vivo drives transcriptional elongation. Genes Dev. 2003;17(11):1392–401. doi: 10.1101/gad.1071803 12782657.

105. Barisic D, Stadler MB, Iurlaro M, Schubeler D. Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors. Nature. 2019;569(7754):136–40. Epub 2019/04/19. doi: 10.1038/s41586-019-1115-5 30996347; PubMed Central PMCID: PMC6522387.

106. Murawska M, Brehm A. CHD chromatin remodelers and the transcription cycle. Transcription. 2011;2(6):244–53. Epub 2012/01/10. doi: 10.4161/trns.2.6.17840 22223048; PubMed Central PMCID: PMC3265784.

107. Tyagi M, Imam N, Verma K, Patel AK. Chromatin remodelers: We are the drivers!! Nucleus. 2016;7(4):388–404. Epub 2016/07/19. doi: 10.1080/19491034.2016.1211217 27429206; PubMed Central PMCID: PMC5039004.

108. Chari S, Umetsu SE, Winandy S. Notch target gene deregulation and maintenance of the leukemogenic phenotype do not require RBP-J kappa in Ikaros null mice. J Immunol. 185(1):410–7. Epub 2010/06/01. jimmunol.0903688 [pii] doi: 10.4049/jimmunol.0903688 20511547.

109. Harker N, Naito T, Cortes M, Hostert A, Hirschberg S, Tolaini M, et al. The CD8alpha gene locus is regulated by the Ikaros family of proteins. Mol Cell. 2002;10(6):1403–15. Epub 2002/12/31. S1097276502007116 [pii]. doi: 10.1016/s1097-2765(02)00711-6 12504015.

110. Ding Y, Zhang B, Payne JL, Song C, Ge Z, Gowda C, et al. Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity. Leukemia. 2019;33(11):2720–31. Epub 2019/05/11. doi: 10.1038/s41375-019-0474-0 31073152; PubMed Central PMCID: PMC6842075.

111. Kim SK, Jung I, Lee H, Kang K, Kim M, Jeong K, et al. Human histone H3K79 methyltransferase DOT1L protein [corrected] binds actively transcribing RNA polymerase II to regulate gene expression. J Biol Chem. 2012;287(47):39698–709. Epub 2012/09/27. doi: 10.1074/jbc.M112.384057 23012353; PubMed Central PMCID: PMC3501035.

112. Schubeler D, MacAlpine DM, Scalzo D, Wirbelauer C, Kooperberg C, van Leeuwen F, et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 2004;18(11):1263–71. Epub 2004/06/04. doi: 10.1101/gad.1198204 15175259; PubMed Central PMCID: PMC420352.

113. Nguyen AT, Zhang Y. The diverse functions of Dot1 and H3K79 methylation. Genes Dev. 2011;25(13):1345–58. Epub 2011/07/05. doi: 10.1101/gad.2057811 21724828; PubMed Central PMCID: PMC3134078.

114. Brown SA, Weirich CS, Newton EM, Kingston RE. Transcriptional activation domains stimulate initiation and elongation at different times and via different residues. EMBO J. 1998;17(11):3146–54. Epub 1998/06/26. doi: 10.1093/emboj/17.11.3146 9606196; PubMed Central PMCID: PMC1170653.

115. Tan KS, Kulkeaw K, Nakanishi Y, Sugiyama D. Expression of cytokine and extracellular matrix mRNAs in fetal hepatic stellate cells. Genes Cells. 2017;22(9):836–44. Epub 2017/08/05. doi: 10.1111/gtc.12517 28776905.

116. Zhao L, Mei Y, Sun Q, Guo L, Wu Y, Yu X, et al. Autologous tumor vaccine modified with recombinant new castle disease virus expressing IL-7 promotes antitumor immune response. J Immunol. 2014;193(2):735–45. Epub 2014/06/20. doi: 10.4049/jimmunol.1400004 24943214.

117. Pope NJ, Bresnick EH. Differential coregulator requirements for function of the hematopoietic transcription factor GATA-1 at endogenous loci. Nucleic Acids Res. 38(7):2190–200. Epub 2010/01/06. gkp1159 [pii] doi: 10.1093/nar/gkp1159 20047963.

118. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45. doi: 10.1093/nar/29.9.e45 11328886.

119. Bottardi S, Guieze R, Bourgoin V, Fotouhi-Ardakani N, Douge A, Darracq A, et al. MNDA controls the expression of MCL-1 and BCL-2 in chronic lymphocytic leukemia cells. Exp Hematol. 2020;88:68–82 e5. Epub 2020/07/19. doi: 10.1016/j.exphem.2020.07.004 32682001.

120. Rao X, Huang X, Zhou Z, Lin X. An improvement of the 2^(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat Bioinforma Biomath. 2013;3(3):71–85. Epub 2013/08/01. 25558171; PubMed Central PMCID: PMC4280562.

Článek vyšel v časopise

PLOS Genetics

2021 Číslo 3
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se