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Chromatin accessibility established by Pou5f3, Sox19b and Nanog primes genes for activity during zebrafish genome activation


Autoři: Máté Pálfy aff001;  Gunnar Schulze aff002;  Eivind Valen aff002;  Nadine L. Vastenhouw aff001
Působiště autorů: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany aff001;  Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway aff002;  Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, Norway aff003
Vyšlo v časopise: Chromatin accessibility established by Pou5f3, Sox19b and Nanog primes genes for activity during zebrafish genome activation. PLoS Genet 16(1): e32767. doi:10.1371/journal.pgen.1008546
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008546

Souhrn

In many organisms, early embryonic development is driven by maternally provided factors until the controlled onset of transcription during zygotic genome activation. The regulation of chromatin accessibility and its relationship to gene activity during this transition remain poorly understood. Here, we generated chromatin accessibility maps with ATAC-seq from genome activation until the onset of lineage specification. During this period, chromatin accessibility increases at regulatory elements. This increase is independent of RNA polymerase II-mediated transcription, with the exception of the hypertranscribed miR-430 locus. Instead, accessibility often precedes the transcription of associated genes. Loss of the maternal transcription factors Pou5f3, Sox19b, and Nanog, which are known to be required for zebrafish genome activation, results in decreased accessibility at regulatory elements. Importantly, the accessibility of regulatory regions, especially when established by Pou5f3, Sox19b and Nanog, is predictive for future transcription. Our results show that the maternally provided transcription factors Pou5f3, Sox19b, and Nanog open up chromatin and prime genes for activity during zygotic genome activation in zebrafish.

Klíčová slova:

Embryos – Gene expression – Gene regulation – Chromatin – Mammalian genomics – Transcription factors – Transcriptional control – Zebrafish


Zdroje

1. Li X-Y, Thomas S, Sabo PJ, Eisen MB, Stamatoyannopoulos JA, Biggin MD. The role of chromatin accessibility in directing the widespread, overlapping patterns of Drosophila transcription factor binding. Genome Biol. 2011;12: R34. doi: 10.1186/gb-2011-12-4-r34 21473766

2. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, et al. The accessible chromatin landscape of the human genome. Nature. 2012;489: 75–82. doi: 10.1038/nature11232 22955617

3. Klemm SL, Shipony Z, Greenleaf WJ. Chromatin accessibility and the regulatory epigenome. Nat Rev Genet. 2019;20: 207–220. doi: 10.1038/s41576-018-0089-8 30675018

4. Wu J, Huang B, Chen H, Yin Q, Liu Y, Xiang Y, et al. The landscape of accessible chromatin in mammalian preimplantation embryos. Nature. 2016;534: 652–657. doi: 10.1038/nature18606 27309802

5. Clark SJ, Argelaguet R, Kapourani C-A, Stubbs TM, Lee HJ, Alda-Catalinas C, et al. scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells. Nat. Commun. 2018;9:781 doi: 10.1038/s41467-018-03149-4 29472610

6. Liu L, Leng L, Liu C, Lu C, Yuan Y, Wu L, et al. An integrated chromatin accessibility and transcriptome landscape of human pre-implantation embryos. Nat Commun. 2019;10: 364. doi: 10.1038/s41467-018-08244-0 30664750

7. McKay DJ, Lieb JD. A common set of DNA regulatory elements shapes Drosophila appendages. Dev Cell. 2013;27: 306–318. doi: 10.1016/j.devcel.2013.10.009 24229644

8. Haines JE, Eisen MB. Patterns of chromatin accessibility along the anterior-posterior axis in the early Drosophila embryo. PLoS Genet. 2018;14: e1007367. doi: 10.1371/journal.pgen.1007367 29727464

9. Lara-Astiaso D, Weiner A, Lorenzo-Vivas E, Zaretsky I, Jaitin DA, David E, et al. Immunogenetics. Chromatin state dynamics during blood formation. Science. 2014;345: 943–949. doi: 10.1126/science.1256271 25103404

10. Blythe SA, Wieschaus EF. Establishment and maintenance of heritable chromatin structure during early Drosophila embryogenesis. Elife. 2016;5.

11. Lu F, Liu Y, Inoue A, Suzuki T, Zhao K, Zhang Y. Establishing Chromatin Regulatory Landscape during Mouse Preimplantation Development. Cell. 2016;165: 1375–1388. doi: 10.1016/j.cell.2016.05.050 27259149

12. Wu J, Xu J, Liu B, Yao G, Wang P, Lin Z, et al. Chromatin analysis in human early development reveals epigenetic transition during ZGA. Nature. 2018;557: 256–260. doi: 10.1038/s41586-018-0080-8 29720659

13. Li L, Guo F, Gao Y, Ren Y, Yuan P, Yan L, et al. Single-cell multi-omics sequencing of human early embryos. Nat Cell Biol. 2018;20: 847–858. doi: 10.1038/s41556-018-0123-2 29915357

14. Kane DA, Kimmel CB. The zebrafish midblastula transition. Development. 1993;119: 447–456. 8287796

15. Lee MT, Bonneau AR, Takacs CM, Bazzini AA, DiVito KR, Fleming ES, et al. Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition. Nature. 2013;503: 360–364. doi: 10.1038/nature12632 24056933

16. White RJ, Collins JE, Sealy IM, Wali N, Dooley CM, Digby Z, et al. A high-resolution mRNA expression time course of embryonic development in zebrafish. Elife. 2017;6.

17. Pálfy M, Joseph SR, Vastenhouw NL. The timing of zygotic genome activation. Curr Opin Genet Dev. 2017;43: 53–60. doi: 10.1016/j.gde.2016.12.001 28088031

18. Vastenhouw NL, Cao WX, Lipshitz HD. The maternal-to-zygotic transition revisited. Development. 2019;146.

19. Heyn P, Kircher M, Dahl A, Kelso J, Tomancak P, Kalinka AT, et al. The earliest transcribed zygotic genes are short, newly evolved, and different across species. Cell Rep. 2014;6: 285–292. doi: 10.1016/j.celrep.2013.12.030 24440719

20. Hilbert L, Sato Y, Kimura H, Jülicher F, Honigmann A, Zaburdaev V, et al. Transcription organizes euchromatin similar to an active microemulsion. bioRxiv. 2018.

21. Hadzhiev Y, Qureshi HK, Wheatley L, Cooper L, Jasiulewicz A, Van Nguyen H, et al. A cell cycle-coordinated Polymerase II transcription compartment encompasses gene expression before global genome activation. Nat Commun. 2019;10: 691. doi: 10.1038/s41467-019-08487-5 30741925

22. Chan SH, Tang Y, Miao L, Darwich-Codore H, Vejnar CE, Beaudoin J-D, et al. Brd4 and P300 Confer Transcriptional Competency during Zygotic Genome Activation. Dev Cell. 2019;49: 867–881.e8. doi: 10.1016/j.devcel.2019.05.037 31211993

23. Leichsenring M, Maes J, Mössner R, Driever W, Onichtchouk D. Pou5f1 transcription factor controls zygotic gene activation in vertebrates. Science. 2013;341: 1005–1009. doi: 10.1126/science.1242527 23950494

24. Xu C, Fan ZP, Müller P, Fogley R, DiBiase A, Trompouki E, et al. Nanog-like Regulates Endoderm Formation through the Mxtx2-Nodal Pathway. Developmental Cell. 2012. pp. 625–638. doi: 10.1016/j.devcel.2012.01.003 22421047

25. Gagnon JA, Obbad K, Schier AF. The primary role of zebrafish nanog is in extra-embryonic tissue. Development. 2018;145.

26. Liu G, Wang W, Hu S, Wang X, Zhang Y. Inherited DNA methylation primes the establishment of accessible chromatin during genome activation. Genome Res. 2018;28: 998–1007. doi: 10.1101/gr.228833.117 29844026

27. Veil M, Yampolsky LY, Grüning B, Onichtchouk D. Pou5f3, SoxB1, and Nanog remodel chromatin on high nucleosome affinity regions at zygotic genome activation. Genome Res. 2019;29: 383–395. doi: 10.1101/gr.240572.118 30674556

28. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods. 2013;10: 1213–1218. doi: 10.1038/nmeth.2688 24097267

29. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9: R137. doi: 10.1186/gb-2008-9-9-r137 18798982

30. Kane DA, Hammerschmidt M, Mullins MC, Maischein HM, Brand M, van Eeden FJ, et al. The zebrafish epiboly mutants. Development. 1996;123: 47–55. 9007228

31. Joseph SR, Pálfy M, Hilbert L, Kumar M, Karschau J, Zaburdaev V, et al. Competition between histone and transcription factor binding regulates the onset of transcription in zebrafish embryos. Elife. 2017;6.

32. Kireeva ML, Walter W, Tchernajenko V, Bondarenko V, Kashlev M, Studitsky VM. Nucleosome remodeling induced by RNA polymerase II: loss of the H2A/H2B dimer during transcription. Mol Cell. 2002;9: 541–552. doi: 10.1016/s1097-2765(02)00472-0 11931762

33. Kulaeva OI, Hsieh F-K, Studitsky VM. RNA polymerase complexes cooperate to relieve the nucleosomal barrier and evict histones. Proc Natl Acad Sci U S A. 2010;107: 11325–11330. doi: 10.1073/pnas.1001148107 20534568

34. van den Berg AA, Depken M. Crowding-induced transcriptional bursts dictate polymerase and nucleosome density profiles along genes. Nucleic Acids Res. 2017;45: 7623–7632. doi: 10.1093/nar/gkx513 28586463

35. Pérez-Rico YA, Boeva V, Mallory AC, Bitetti A, Majello S, Barillot E, et al. Comparative analyses of super-enhancers reveal conserved elements in vertebrate genomes. Genome Res. 2017;27: 259–268. doi: 10.1101/gr.203679.115 27965291

36. Pauli A, Valen E, Lin MF, Garber M, Vastenhouw NL, Levin JZ, et al. Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. Genome Res. 2012;22: 577–591. doi: 10.1101/gr.133009.111 22110045

37. Blader P, Lam CS, Rastegar S, Scardigli R, Nicod J-C, Simplicio N, et al. Conserved and acquired features of neurogenin1 regulation. Development. 2004;131: 5627–5637. doi: 10.1242/dev.01455 15496438

38. Harvey SA, Tümpel S, Dubrulle J, Schier AF, Smith JC. no tail integrates two modes of mesoderm induction. Development. 2010;137: 1127–1135. doi: 10.1242/dev.046318 20215349

39. Kurokawa D, Sakurai Y, Inoue A, Nakayama R, Takasaki N, Suda Y, et al. Evolutionary constraint on Otx2 neuroectoderm enhancers-deep conservation from skate to mouse and unique divergence in teleost. Proceedings of the National Academy of Sciences. 2006. pp. 19350–19355.

40. Jao L-E, Wente SR, Chen W. Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. Proc Natl Acad Sci U S A. 2013;110: 13904–13909. doi: 10.1073/pnas.1308335110 23918387

41. Rossi A, Kontarakis Z, Gerri C, Nolte H, Hölper S, Krüger M, et al. Genetic compensation induced by deleterious mutations but not gene knockdowns. Nature. 2015;524: 230–233. doi: 10.1038/nature14580 26168398

42. El-Brolosy MA, Kontarakis Z, Rossi A, Kuenne C, Günther S, Fukuda N, et al. Genetic compensation triggered by mutant mRNA degradation. Nature. 2019;568: 193–197. doi: 10.1038/s41586-019-1064-z 30944477

43. Anderson JL, Mulligan TS, Shen M-C, Wang H, Scahill CM, Tan FJ, et al. mRNA processing in mutant zebrafish lines generated by chemical and CRISPR-mediated mutagenesis produces unexpected transcripts that escape nonsense-mediated decay. PLoS Genet. 2017;13: e1007105. doi: 10.1371/journal.pgen.1007105 29161261

44. Reim G, Brand M. Maternal control of vertebrate dorsoventral axis formation and epiboly by the POU domain protein Spg/Pou2/Oct4. Development. 2006;133: 2757–2770. doi: 10.1242/dev.02391 16775002

45. Reim G, Mizoguchi T, Stainier DY, Kikuchi Y, Brand M. The POU domain protein spg (pou2/Oct4) is essential for endoderm formation in cooperation with the HMG domain protein casanova. Dev Cell. 2004;6: 91–101. doi: 10.1016/s1534-5807(03)00396-4 14723850

46. Lunde K, Belting H-G, Driever W. Zebrafish pou5f1/pou2, homolog of mammalian Oct4, functions in the endoderm specification cascade. Curr Biol. 2004;14: 48–55. doi: 10.1016/j.cub.2003.11.022 14711414

47. Okuda Y, Ogura E, Kondoh H, Kamachi Y. B1 SOX coordinate cell specification with patterning and morphogenesis in the early zebrafish embryo. PLoS Genet. 2010;6: e1000936. doi: 10.1371/journal.pgen.1000936 20463883

48. Veil M, Schaechtle MA, Gao M, Kirner V, Buryanova L, Grethen R, et al. Maternal Nanog is required for zebrafish embryo architecture and for cell viability during gastrulation. Development. 2018;145.

49. Mayran A, Drouin J. Pioneer transcription factors shape the epigenetic landscape. J Biol Chem. 2018;293: 13795–13804. doi: 10.1074/jbc.R117.001232 29507097

50. Soufi A, Garcia MF, Jaroszewicz A, Osman N, Pellegrini M, Zaret KS. Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell. 2015;161: 555–568. doi: 10.1016/j.cell.2015.03.017 25892221

51. Meers MP, Janssens DH, Henikoff S. Pioneer Factor-Nucleosome Binding Events during Differentiation Are Motif Encoded. Mol Cell. 2019;75: 562–575.e5. doi: 10.1016/j.molcel.2019.05.025 31253573

52. Bogdanović O, Fernandez-Miñán A, Tena JJ. Dynamics of enhancer chromatin signatures mark the transition from pluripotency to cell specification during embryogenesis. Genome Res. 2012. 10: 2043–53.

53. Gentsch GE, Spruce T, Owens NDL, Smith JC. Maternal pluripotency factors initiate extensive chromatin remodelling to predefine first response to inductive signals. Nat Commun. 2019;10: 4269. doi: 10.1038/s41467-019-12263-w 31537794

54. Cusanovich DA, Daza R, Adey A, Pliner HA, Christiansen L, Gunderson KL, et al. Multiplex single cell profiling of chromatin accessibility by combinatorial cellular indexing. Science. 2015;348: 910–914. doi: 10.1126/science.aab1601 25953818

55. Buenrostro JD, Wu B, Litzenburger UM, Ruff D, Gonzales ML, Snyder MP, et al. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature. 2015;523: 486–490. doi: 10.1038/nature14590 26083756

56. Farrell JA, Wang Y, Riesenfeld SJ, Shekhar K, Regev A, Schier AF. Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis. Science. 2018;360.

57. Wagner DE, Weinreb C, Collins ZM, Briggs JA, Megason SG, Klein AM. Single-cell mapping of gene expression landscapes and lineage in the zebrafish embryo. Science. 2018;360: 981–987. doi: 10.1126/science.aar4362 29700229

58. Cusanovich DA, Reddington JP, Garfield DA, Daza RM, Aghamirzaie D, Marco-Ferreres R, et al. The cis-regulatory dynamics of embryonic development at single-cell resolution. Nature. 2018;555: 538–542. doi: 10.1038/nature25981 29539636

59. Lippok B, Song S, Driever W. Pou5f1 protein expression and posttranslational modification during early zebrafish development. Dev Dyn. 2014;243: 468–477. doi: 10.1002/dvdy.24079 24130110

60. Fenouil R, Cauchy P, Koch F, Descostes N, Cabeza JZ, Innocenti C, et al. CpG islands and GC content dictate nucleosome depletion in a transcription-independent manner at mammalian promoters. Genome Res. 2012;22: 2399–2408. doi: 10.1101/gr.138776.112 23100115

61. Fursova NA, Blackledge NP, Klose RJ. Polycomb repressive complex 1 shapes the nucleosome landscape but not accessibility at target genes. Genome Res. 2018;10: 1494–1507.

62. Sato Y, Hilbert L, Oda H, Wan Y, Heddleston JM, Chew T-L, et al. Histone H3K27 acetylation precedes active transcription during zebrafish zygotic genome activation as revealed by live-cell analysis. Development. 2019;146.

63. Vastenhouw NL, Zhang Y, Woods IG, Imam F, Regev A, Liu XS, et al. Chromatin signature of embryonic pluripotency is established during genome activation. Nature. 2010;464: 922–926. doi: 10.1038/nature08866 20336069

64. Lindeman LC, Andersen IS, Reiner AH, Li N, Aanes H, Østrup O, et al. Prepatterning of developmental gene expression by modified histones before zygotic genome activation. Dev Cell. 2011;21: 993–1004. doi: 10.1016/j.devcel.2011.10.008 22137762

65. Zhang B, Wu X, Zhang W, Shen W, Sun Q, Liu K, et al. Widespread Enhancer Dememorization and Promoter Priming during Parental-to-Zygotic Transition. Mol Cell. 2018;72: 673–686.e6. doi: 10.1016/j.molcel.2018.10.017 30444999

66. Murphy PJ, Wu SF, James CR, Wike CL, Cairns BR. Placeholder Nucleosomes Underlie Germline-to-Embryo DNA Methylation Reprogramming. Cell. 2018;172: 993–1006.e13. doi: 10.1016/j.cell.2018.01.022 29456083

67. Kaaij LJT, Mokry M, Zhou M, Musheev M, Geeven G, Melquiond ASJ, et al. Enhancers reside in a unique epigenetic environment during early zebrafish development. Genome Biol. 2016;17: 146. doi: 10.1186/s13059-016-1013-1 27381023

68. Andersen IS, Reiner AH, Aanes H, Aleström P, Collas P. Developmental features of DNA methylation during activation of the embryonic zebrafish genome. Genome Biol. 2012;13: R65. doi: 10.1186/gb-2012-13-7-r65 22830626

69. Zhang Y, Vastenhouw NL, Feng J, Fu K, Wang C, Ge Y, et al. Canonical nucleosome organization at promoters forms during genome activation. Genome Res. 2014;24: 260–266. doi: 10.1101/gr.157750.113 24285721

70. Li X-Y, Harrison MM, Villalta JE, Kaplan T, Eisen MB. Establishment of regions of genomic activity during the Drosophila maternal to zygotic transition. Elife. 2014;3.

71. Schulz KN, Bondra ER, Moshe A, Villalta JE, Lieb JD, Kaplan T, et al. Zelda is differentially required for chromatin accessibility, transcription factor binding, and gene expression in the early Drosophila embryo. Genome Res. 2015;25: 1715–1726. doi: 10.1101/gr.192682.115 26335634

72. Soufi A, Donahue G, Zaret KS. Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell. 2012;151: 994–1004. doi: 10.1016/j.cell.2012.09.045 23159369

73. Ladam F, Stanney W, Donaldson IJ, Yildiz O, Bobola N, Sagerström CG. TALE factors use two distinct functional modes to control an essential zebrafish gene expression program. Elife. 2018;7.

74. Stanney W, Ladam F, Donaldson IJ, Parsons TJ. TALE and NF-Y co-occupancy marks enhancers of developmental control genes during zygotic genome activation in zebrafish. bioRxiv. 2019.

75. Oldfield AJ, Yang P, Conway AE, Cinghu S, Freudenberg JM, Yellaboina S, et al. Histone-fold domain protein NF-Y promotes chromatin accessibility for cell type-specific master transcription factors. Mol Cell. 2014;55: 708–722. doi: 10.1016/j.molcel.2014.07.005 25132174

76. Jänes J, Dong Y, Schoof M, Serizay J, Appert A, Cerrato C, et al. Chromatin accessibility dynamics across C. elegans development and ageing. Elife. 2018;7.

77. Pliner HA, Packer JS, McFaline-Figueroa JL, Cusanovich DA, Daza RM, Aghamirzaie D, et al. Cicero Predicts cis-Regulatory DNA Interactions from Single-Cell Chromatin Accessibility Data. Mol Cell. 2018;71: 858–871.e8. doi: 10.1016/j.molcel.2018.06.044 30078726

78. 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.:

79. Esch D, Vahokoski J, Groves MR, Pogenberg V, Cojocaru V, Vom Bruch H, et al. A unique Oct4 interface is crucial for reprogramming to pluripotency. Nat Cell Biol. 2013;15: 295–301. doi: 10.1038/ncb2680 23376973

80. Tapia N, Reinhardt P, Duemmler A, Wu G, Araúzo-Bravo MJ, Esch D, et al. Reprogramming to pluripotency is an ancient trait of vertebrate Oct4 and Pou2 proteins. Nat Commun. 2012;3: 1279. doi: 10.1038/ncomms2229 23232409

81. Nelson AC, Cutty SJ, Niini M, Stemple DL, Flicek P, Houart C, et al. Global identification of Smad2 and Eomesodermin targets in zebrafish identifies a conserved transcriptional network in mesendoderm and a novel role for Eomesodermin in repression of ectodermal gene expression. BMC Biol. 2014;12: 81. doi: 10.1186/s12915-014-0081-5 25277163

82. Dubrulle J, Jordan BM, Akhmetova L, Farrell JA, Kim S-H, Solnica-Krezel L, et al. Response to Nodal morphogen gradient is determined by the kinetics of target gene induction. Elife. 2015;4.

83. Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF. Stages of embryonic development of the zebrafish. Dev Dyn. 1995;203: 253–310. doi: 10.1002/aja.1002030302 8589427

84. Montague TG, Cruz JM, Gagnon JA, Church GM, Valen E. CHOPCHOP: a CRISPR/Cas9 and TALEN web tool for genome editing. Nucleic Acids Res. 2014;42: W401–7. doi: 10.1093/nar/gku410 24861617

85. Labun K, Montague TG, Gagnon JA, Thyme SB, Valen E. CHOPCHOP v2: a web tool for the next generation of CRISPR genome engineering. Nucleic Acids Res. 2016;44: W272–6. doi: 10.1093/nar/gkw398 27185894

86. Buenrostro JD, Wu B, Chang HY, Greenleaf WJ. ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide. Curr Protoc Mol Biol. 2015;109: 21.29.1–9.

87. Link V, Shevchenko A, Heisenberg C-P. Proteomics of early zebrafish embryos. BMC Dev Biol. 2006;6: 1. doi: 10.1186/1471-213X-6-1 16412219

88. Nelson AC, Cutty SJ, Gasiunas SN, Deplae I, Stemple DL, Wardle FC. In Vivo Regulation of the Zebrafish Endoderm Progenitor Niche by T-Box Transcription Factors. Cell Reports. 2017. pp. 2782–2795. doi: 10.1016/j.celrep.2017.06.011 28658625

89. Bailey TL, Boden M, Buske FA, Frith M, Grant CE, Clementi L, et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 2009;37: W202–8. doi: 10.1093/nar/gkp335 19458158

90. Khan A, Fornes O, Stigliani A, Gheorghe M, Castro-Mondragon JA, van der Lee R, et al. JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. Nucleic Acids Research. 2018. pp. D260–D266. doi: 10.1093/nar/gkx1126 29140473

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