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Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans


Autoři: Naomi Shomer aff001;  Alexandre Zacharie Kadhim aff001;  Jennifer Margaret Grants aff001;  Xuanjin Cheng aff002;  Deema Alhusari aff001;  Forum Bhanshali aff002;  Amy Fong-Yuk Poon aff002;  Michelle Ying Ya Lee aff002;  Anik Muhuri aff002;  Jung In Park aff002;  James Shih aff002;  Dongyeop Lee aff004;  Seung-Jae V. Lee aff005;  Francis Christopher Lynn aff003;  Stefan Taubert aff001
Působiště autorů: Graduate Program in Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada aff001;  Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada aff002;  British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada aff003;  Department of Life Sciences, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, South Korea aff004;  Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Yuseong-Gu, Daejeon, South Korea aff005;  Department of Surgery, The University of British Columbia, Vancouver, British Columbia, Canada aff006;  Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada aff007
Vyšlo v časopise: Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008508
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008508

Souhrn

Zinc is essential for cellular functions as it is a catalytic and structural component of many proteins. In contrast, cadmium is not required in biological systems and is toxic. Zinc and cadmium levels are closely monitored and regulated as their excess causes cell stress. To maintain homeostasis, organisms induce metal detoxification gene programs through stress responsive transcriptional regulatory complexes. In Caenorhabditis elegans, the MDT-15 subunit of the evolutionarily conserved Mediator transcriptional coregulator is required to induce genes upon exposure to excess zinc and cadmium. However, the regulatory partners of MDT-15 in this response, its role in cellular and physiological stress adaptation, and the putative role for mammalian MED15 in the metal stress responses remain unknown. Here, we show that MDT-15 interacts physically and functionally with the Nuclear Hormone Receptor HIZR-1 to promote molecular, cellular, and organismal adaptation to cadmium and excess zinc. Using gain- and loss-of-function mutants and qRT-PCR and reporter analysis, we find that mdt-15 and hizr-1 cooperate to induce zinc and cadmium responsive genes. Moreover, the two proteins interact physically in yeast-two-hybrid assays and this interaction is enhanced by the addition of zinc or cadmium, the former a known ligand of HIZR-1. Functionally, mdt-15 and hizr-1 mutants show defective storage of excess zinc in the gut and are hypersensitive to zinc-induced reductions in egg-laying. Furthermore, mdt-15 but not hizr-1 mutants are hypersensitive to cadmium-induced reductions in egg-laying, suggesting potential divergence of regulatory pathways. Lastly, mammalian MDT-15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a cadmium and zinc-stimulated fashion, and human MED15 is required to induce a metallothionein gene in lung adenocarcinoma cells exposed to cadmium. Collectively, our data show that mdt-15 and hizr-1 cooperate to regulate cadmium detoxification and zinc storage and that this mechanism is at least partially conserved in mammals.

Klíčová slova:

Cadmium – Caenorhabditis elegans – Gene expression – Gene regulation – RNA interference – Transcription factors – Transcriptional control – Zinc


Zdroje

1. Hambidge KM, Miller LV, Westcott JE, Sheng X, Krebs NF. Zinc bioavailability and homeostasis. Am J Clin Nutr. 2010;91: 1478S–1483S. doi: 10.3945/ajcn.2010.28674I 20200254

2. Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev. 1993;73: 79–118. doi: 10.1152/physrev.1993.73.1.79 8419966

3. Murakami M, Hirano T. Intracellular zinc homeostasis and zinc signaling. Cancer Sci. 2008;99: 1515–1522. doi: 10.1111/j.1349-7006.2008.00854.x 18754861

4. Andreini C, Banci L, Bertini I, Rosato A. Zinc through the three domains of life. J Proteome Res. 2006;5: 3173–3178. doi: 10.1021/pr0603699 17081069

5. Fukada T, Yamasaki S, Nishida K, Murakami M, Hirano T. Zinc homeostasis and signaling in health and diseases: Zinc signaling. J Biol Inorg Chem. 2011;16: 1123–1134. doi: 10.1007/s00775-011-0797-4 21660546

6. Plum LM, Rink L, Haase H. The essential toxin: impact of zinc on human health. Int J Environ Res Public Health. 2010;7: 1342–1365. doi: 10.3390/ijerph7041342 20617034

7. Thévenod F, Lee W-K. Cadmium and cellular signaling cascades: interactions between cell death and survival pathways. Arch Toxicol. 2013;87: 1743–1786. doi: 10.1007/s00204-013-1110-9 23982889

8. Joseph P. Mechanisms of cadmium carcinogenesis. Toxicol Appl Pharmacol. 2009;238: 272–279. doi: 10.1016/j.taap.2009.01.011 19371617

9. Maret W. The Metals in the Biological Periodic System of the Elements: Concepts and Conjectures. Int J Mol Sci. 2016;17. doi: 10.3390/ijms17010066 26742035

10. Dong J, Song MO, Freedman JH. Identification and characterization of a family of Caenorhabditis elegans genes that is homologous to the cadmium-responsive gene cdr-1. Biochim Biophys Acta. 2005;1727: 16–26. doi: 10.1016/j.bbaexp.2004.11.007 15652154

11. Brzóska MM, Moniuszko-Jakoniuk J. Interactions between cadmium and zinc in the organism. Food Chem Toxicol. 2001;39: 967–980. doi: 10.1016/s0278-6915(01)00048-5 11524135

12. Park C, Jeong J. Synergistic cellular responses to heavy metal exposure: A minireview. Biochim Biophys Acta. 2018;1862: 1584–1591. doi: 10.1016/j.bbagen.2018.04.003 29631058

13. Dietrich N, Tan C-H, Cubillas C, Earley BJ, Kornfeld K. Insights into zinc and cadmium biology in the nematode Caenorhabditis elegans. Arch Biochem Biophys. 2016;611: 120–133. doi: 10.1016/j.abb.2016.05.021 27261336

14. Chabosseau P, Rutter GA. Zinc and diabetes. Arch Biochem Biophys. 2016;611: 79–85. doi: 10.1016/j.abb.2016.05.022 27262257

15. Ehrensberger KM, Bird AJ. Hammering out details: regulating metal levels in eukaryotes. Trends Biochem Sci. 2011;36: 524–531. doi: 10.1016/j.tibs.2011.07.002 21840721

16. Choi S, Bird AJ. Zinc'ing sensibly: controlling zinc homeostasis at the transcriptional level. Metallomics. 2014;6: 1198–1215. doi: 10.1039/c4mt00064a 24722954

17. Günther V, Lindert U, Schaffner W. The taste of heavy metals: gene regulation by MTF-1. Biochim Biophys Acta. 2012;1823: 1416–1425. doi: 10.1016/j.bbamcr.2012.01.005 22289350

18. Coneyworth LJ, Jackson KA, Tyson J, Bosomworth HJ, van der Hagen E, Hann GM, et al. Identification of the human zinc transcriptional regulatory element (ZTRE): a palindromic protein-binding DNA sequence responsible for zinc-induced transcriptional repression. J Biol Chem. 2012;287: 36567–36581. doi: 10.1074/jbc.M112.397000 22902622

19. Roh HC, Dimitrov I, Deshmukh K, Zhao G, Warnhoff K, Cabrera D, et al. A modular system of DNA enhancer elements mediates tissue-specific activation of transcription by high dietary zinc in C. elegans. Nucleic Acids Res. 2015;43: 803–816. doi: 10.1093/nar/gku1360 25552416

20. Warnhoff K, Roh HC, Kocsisova Z, Tan C-H, Morrison A, Croswell D, et al. The Nuclear Receptor HIZR-1 Uses Zinc as a Ligand to Mediate Homeostasis in Response to High Zinc. Sengupta P, Tissenbaum H, editors. PLoS Biol. Public Library of Science; 2017;15: e2000094. doi: 10.1371/journal.pbio.2000094 28095401

21. Taubert S, Ward JD, Yamamoto KR. Nuclear hormone receptors in nematodes: evolution and function. Mol Cell Endocrinol. 2011;334: 49–55. doi: 10.1016/j.mce.2010.04.021 20438802

22. O'Malley BW, Qin J, Lanz RB. Cracking the coregulator codes. Current Opinion in Cell Biology. 2008;20: 310–315. doi: 10.1016/j.ceb.2008.04.005 18499426

23. Spiegelman BM, Heinrich R. Biological control through regulated transcriptional coactivators. Cell. 2004;119: 157–167. doi: 10.1016/j.cell.2004.09.037 15479634

24. Vihervaara A, Duarte FM, Lis JT. Molecular mechanisms driving transcriptional stress responses. Nat Rev Genet. 2018;19: 385–397. doi: 10.1038/s41576-018-0001-6 29556092

25. Allen BL, Taatjes DJ. The Mediator complex: a central integrator of transcription. Nat Rev Mol Cell Biol. 2015;16: 155–166. doi: 10.1038/nrm3951 25693131

26. Grants JM, Goh GYS, Taubert S. The Mediator complex of Caenorhabditis elegans: insights into the developmental and physiological roles of a conserved transcriptional coregulator. Nucleic Acids Res. 2015;43: 2442–2453. doi: 10.1093/nar/gkv037 25634893

27. Naar AM, Thakur JK. Nuclear receptor-like transcription factors in fungi. Genes Dev. 2009;23: 419–432. doi: 10.1101/gad.1743009 19240130

28. Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn Y-J, et al. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature. 2016;530: 485–489. doi: 10.1038/nature16963 26886795

29. Fant CB, Taatjes DJ. Regulatory functions of the Mediator kinases CDK8 and CDK19. transcription. 2018;153: 1–15. doi: 10.1080/21541264.2018.1556915 30585107

30. Galbraith MD, Allen MA, Bensard CL, Wang X, Schwinn MK, Qin B, et al. HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia. Cell. 2013;153: 1327–1339. doi: 10.1016/j.cell.2013.04.048 23746844

31. Bose S, Dutko JA, Zitomer RS. Genetic factors that regulate the attenuation of the general stress response of yeast. Genetics. 2005;169: 1215–1226. doi: 10.1534/genetics.104.034603 15545648

32. Marr MT, Isogai Y, Wright KJ, Tjian R. Coactivator cross-talk specifies transcriptional output. Genes Dev. 2006;20: 1458–1469. doi: 10.1101/gad.1418806 16751183

33. Taubert S, Hansen M, Van Gilst MR, Cooper SB, Yamamoto KR. The Mediator subunit MDT-15 confers metabolic adaptation to ingested material. PLoS Genet. 2008;4: e1000021. doi: 10.1371/journal.pgen.1000021 18454197

34. Taubert S, Van Gilst MR, Hansen M, Yamamoto KR. A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans. Genes Dev. 2006;20: 1137–1149. doi: 10.1101/gad.1395406 16651656

35. Arda HE, Taubert S, Macneil LT, Conine CC, Tsuda B, Van Gilst M, et al. Functional modularity of nuclear hormone receptors in a Caenorhabditis elegans metabolic gene regulatory network. Molecular Systems Biology. 2010;6: 367. doi: 10.1038/msb.2010.23 20461074

36. Goh GYS, Winter JJ, Bhanshali F, Doering KRS, Lai R, Lee K, et al. NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting. Aging Cell. 2018;17: e12743. doi: 10.1111/acel.12743 29508513

37. Hu Q, D'Amora DR, Macneil LT, Walhout AJM, Hu Q. The Caenorhabditis elegans Oxidative Stress Response Requires the NHR-49 Transcription Factor. G3 (Bethesda). 2018;8: 3857–3863. doi: 10.1534/g3.118.200727 30297383

38. Grants JM, Ying LTL, Yoda A, You CC, Okano H, Sawa H, et al. The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans. Genetics. Genetics; 2016;202: 583–599. doi: 10.1534/genetics.115.180265 26715664

39. van de Peppel J, Kettelarij N, van Bakel H, Kockelkorn TTJP, van Leenen D, Holstege FCP. Mediator expression profiling epistasis reveals a signal transduction pathway with antagonistic submodules and highly specific downstream targets. Molecular Cell. 2005;19: 511–522. doi: 10.1016/j.molcel.2005.06.033 16109375

40. Liao VH-C, Dong J, Freedman JH. Molecular characterization of a novel, cadmium-inducible gene from the nematode Caenorhabditis elegans. A new gene that contributes to the resistance to cadmium toxicity. J Biol Chem. 2002;277: 42049–42059. doi: 10.1074/jbc.M206740200 12189149

41. Hall J, Haas KL, Freedman JH. Role of MTL-1, MTL-2, and CDR-1 in mediating cadmium sensitivity in Caenorhabditis elegans. Toxicol Sci. 2012;128: 418–426. doi: 10.1093/toxsci/kfs166 22552775

42. Tvermoes BE, Boyd WA, Freedman JH. Molecular characterization of numr-1 and numr-2: genes that increase both resistance to metal-induced stress and lifespan in Caenorhabditis elegans. J Cell Sci. 2010;123: 2124–2134. doi: 10.1242/jcs.065433 20501697

43. Cui Y, McBride SJ, Boyd WA, Alper S, Freedman JH. Toxicogenomic analysis of Caenorhabditis elegans reveals novel genes and pathways involved in the resistance to cadmium toxicity. Genome Biol. BioMed Central Ltd; 2007;8: R122. doi: 10.1186/gb-2007-8-6-r122 17592649

44. Wu C-W, Wimberly K, Pietras A, Dodd W, Atlas MB, Choe KP. RNA processing errors triggered by cadmium and integrator complex disruption are signals for environmental stress. BMC Biol. BioMed Central; 2019;17: 56–14. doi: 10.1186/s12915-019-0675-z 31311534

45. Kormish JD, Gaudet J, Mcghee JD. Development of the C. elegans digestive tract. Current Opinion in Genetics & Development. 2010;20: 346–354. doi: 10.1016/j.gde.2010.04.012 20570129

46. Svensk E, Ståhlman M, Andersson C-H, Johansson M, Borén J, Pilon M. PAQR-2 Regulates Fatty Acid Desaturation during Cold Adaptation in C. elegans. PLoS Genet. 2013;9: e1003801. doi: 10.1371/journal.pgen.1003801 24068966

47. Lee D, An SWA, Jung Y, Yamaoka Y, Ryu Y, Goh GYS, et al. MDT-15/MED15 permits longevity at low temperature via enhancing lipidostasis and proteostasis. PLoS Biol. 2019;17: e3000415. doi: 10.1371/journal.pbio.3000415 31408455

48. Goh GYS, Martelli KL, Parhar KS, Kwong AWL, Wong MA, Mah A, et al. The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans. Aging Cell. 2014;13: 70–79. doi: 10.1111/acel.12154 23957350

49. Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun Z-Y, Watts JL, et al. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature. 2006;442: 700–704. doi: 10.1038/nature04942 16799563

50. Roh HC, Collier S, Guthrie J, Robertson JD, Kornfeld K. Lysosome-related organelles in intestinal cells are a zinc storage site in C. elegans. Cell Metabolism. 2012;15: 88–99. doi: 10.1016/j.cmet.2011.12.003 22225878

51. Lee K, Goh GYS, Wong MA, Klassen TL, Taubert S. Gain-of-Function Alleles in Caenorhabditis elegans Nuclear Hormone Receptor nhr-49 Are Functionally Distinct. PLoS ONE. 2016;11: e0162708. doi: 10.1371/journal.pone.0162708 27618178

52. Hou NS, Gutschmidt A, Choi DY, Pather K, Shi X, Watts JL, et al. Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo. Proc Natl Acad Sci USA. 2014;111: E2271–80. doi: 10.1073/pnas.1318262111 24843123

53. Brock TJ, Browse J, Watts JL. Genetic regulation of unsaturated fatty acid composition in C. elegans. PLoS Genet. 2006;2: e108. doi: 10.1371/journal.pgen.0020108 16839188

54. Bourbon H-M, Aguilera A, Ansari AZ, Asturias FJ, Berk AJ, Björklund S, et al. A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II. Molecular Cell. 2004;14: 553–557. doi: 10.1016/j.molcel.2004.05.011 15175151

55. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Arsenic, metals, fibres, and dusts. IARC Monogr Eval Carcinog Risks Hum. 2012;100: 11–465. 23189751

56. Beveridge R, Pintos J, Parent M-É, Asselin J, Siemiatycki J. Lung cancer risk associated with occupational exposure to nickel, chromium VI, and cadmium in two population-based case-control studies in Montreal. Am J Ind Med. 2010;53: 476–485. doi: 10.1002/ajim.20801 20187007

57. Zhao W-J, Zhang Z-J, Zhu Z-Y, Song Q, Zheng W-J, Hu X, et al. Time-dependent response of A549 cells upon exposure to cadmium. J Appl Toxicol. 2018;: 1–10. doi: 10.1002/jat.3665 30051583

58. Rutter GA, Chabosseau P, Bellomo EA, Maret W, Mitchell RK, Hodson DJ, et al. Intracellular zinc in insulin secretion and action: a determinant of diabetes risk? Proc Nutr Soc. 2016;75: 61–72. doi: 10.1017/S0029665115003237 26365743

59. Li YV. Zinc and insulin in pancreatic beta-cells. Endocrine. 2014;45: 178–189. doi: 10.1007/s12020-013-0032-x 23979673

60. Chen W, Roeder RG. Mediator-dependent nuclear receptor function. Seminars in Cell and Developmental Biology. 2011;22: 749–758. doi: 10.1016/j.semcdb.2011.07.026 21854863

61. Mao X, Kim B-E, Wang F, Eide DJ, Petris MJ. A histidine-rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity. J Biol Chem. American Society for Biochemistry and Molecular Biology; 2007;282: 6992–7000. doi: 10.1074/jbc.M610552200 17202136

62. Bafaro E, Liu Y, Xu Y, Dempski RE. The emerging role of zinc transporters in cellular homeostasis and cancer. Signal Transduct Target Ther. 2017;2: 17029. doi: 10.1038/sigtrans.2017.29 29218234

63. Brelivet Y, Kammerer S, Rochel N, Poch O, Moras D. Signature of the oligomeric behaviour of nuclear receptors at the sequence and structural level. EMBO Rep. 2004;5: 423–429. doi: 10.1038/sj.embor.7400119 15105832

64. Thakur JK, Arthanari H, Yang F, Chau KH, Wagner G, Näär AM. Mediator subunit Gal11p/MED15 is required for fatty acid-dependent gene activation by yeast transcription factor Oaf1p. J Biol Chem. 2009;284: 4422–4428. doi: 10.1074/jbc.M808263200 19056732

65. Thakur JK, Arthanari H, Yang F, Pan S-J, Fan X, Breger J, et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature. 2008;452: 604–609. doi: 10.1038/nature06836 18385733

66. Yamazaki K, Kuromitsu J, Tanaka I. Microarray analysis of gene expression changes in mouse liver induced by peroxisome proliferator- activated receptor alpha agonists. Biochem Biophys Res Commun. 2002;290: 1114–1122. doi: 10.1006/bbrc.2001.6319 11798191

67. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974;77: 71–94. 4366476

68. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, et al. Primer3—new capabilities and interfaces. Nucleic Acids Res. 2012;40: e115–e11 5. doi: 10.1093/nar/gks596 22730293

69. Stuart GW, Searle PF, Chen HY, Brinster RL, Palmiter RD. A 12-base-pair DNA motif that is repeated several times in metallothionein gene promoters confers metal regulation to a heterologous gene. Proceedings of the National Academy of Sciences. 1984;81: 7318–7322.

70. Sorger PK. Heat shock factor and the heat shock response. Cell. 1991;65: 363–366. doi: 10.1016/0092-8674(91)90452-5 2018972

71. Blackwell TK, Bowerman B, Priess JR, Weintraub H. Formation of a monomeric DNA binding domain by Skn-1 bZIP and homeodomain elements. Science. 1994;266: 621–628. doi: 10.1126/science.7939715 7939715

72. Chen X, Chu M, Giedroc DP. MRE-Binding transcription factor-1: weak zinc-binding finger domains 5 and 6 modulate the structure, affinity, and specificity of the metal-response element complex. Biochemistry. 1999;38: 12915–12925. doi: 10.1021/bi9913000 10504263

73. Furuyama T, Nakazawa T, Nakano I, Mori N. Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem J. Portland Press Ltd; 2000;349: 629–634.

74. Smale ST, Kadonaga JT. The RNA polymerase II core promoter. Annu Rev Biochem. 2003;72: 449–479. doi: 10.1146/annurev.biochem.72.121801.161520 12651739

75. An JH, Blackwell TK. SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev. 2003;17: 1882–1893. doi: 10.1101/gad.1107803 12869585

76. Shen C, Nettleton D, Jiang M, Kim SK, Powell-Coffman JA. Roles of the HIF-1 hypoxia-inducible factor during hypoxia response in Caenorhabditis elegans. J Biol Chem. 2005;280: 20580–20588. doi: 10.1074/jbc.M501894200 15781453

77. Mcghee JD, Sleumer MC, Bilenky M, Wong K, McKay SJ, Goszczynski B, et al. The ELT-2 GATA-factor and the global regulation of transcription in the C. elegans intestine. Dev Biol. 2007;302: 627–645. doi: 10.1016/j.ydbio.2006.10.024 17113066

78. Chiang W-C, Ching T-T, Lee HC, Mousigian C, Hsu A-L. HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity. Cell. 2012;148: 322–334. doi: 10.1016/j.cell.2011.12.019 22265419

79. Rueden CT, Schindelin J, Hiner MC, DeZonia BE, Walter AE, Arena ET, et al. ImageJ2: ImageJ for the next generation of scientific image data. BMC Bioinformatics. 2017;18: 529. doi: 10.1186/s12859-017-1934-z 29187165

80. Sabatini PV, Speckmann T, Nian C, Glavas MM, Wong CK, Yoon JS, et al. Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells. Cell Rep. 2018;22: 163–174. doi: 10.1016/j.celrep.2017.12.033 29298418

81. Johnson DS, Mortazavi A, Myers RM, Wold B. Genome-wide mapping of in vivo protein-DNA interactions. Science. 2007;316: 1497–1502. doi: 10.1126/science.1141319 17540862

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