Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements

English version České info

Drug response varies between individuals and can be caused by genetic factors. Nucleotide variation in gene regulatory elements can have a significant effect on drug response, but due to the difficulty in identifying these elements, they remain understudied. Here, we used various genomic assays to analyze human liver cells treated with or without the antibiotic rifampin and identified drug-induced regulatory elements genome-wide. The testing of numerous active promoters in human liver cells showed only a few to be induced by rifampin treatment. A similar analysis of enhancers found several of them to be induced by the drug. Nucleotide variants in one of these enhancers were found to alter its activity. Combined, this work identifies numerous novel gene regulatory elements that can be activated due to drug response and thus provides candidate sequences in the human genome where nucleotide variation can lead to differences in drug response. It also provides a universally applicable method to detect these elements for other drugs.

Vyšlo v časopise: Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004648
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004648

Souhrn

Zdroje

1. LazarouJ, PomeranzBH, CoreyPN (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279: 1200–1205.

2. UrquhartBL, TironaRG, KimRB (2007) Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. J Clin Pharmacol 47: 566–578.

3. WangD, PoiMJ, SunX, GaedigkA, LeederJS, et al. (2014) Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity. Hum Mol Genet 23: 268–278.

4. SanfordJC, GuoY, SadeeW, WangD (2013) Regulatory polymorphisms in CYP2C19 affecting hepatic expression. Drug Metabol Drug Interact 28: 23–30.

5. KuehlP, ZhangJ, LinY, LambaJ, AssemM, et al. (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27: 383–391.

6. YenT, NightingaleBN, BurnsJC, SullivanDR, StewartPM (2003) Butyrylcholinesterase (BCHE) genotyping for post-succinylcholine apnea in an Australian population. Clin Chem 49: 1297–1308.

7. SchaeffelerE, FischerC, BrockmeierD, WernetD, MoerikeK, et al. (2004) Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 14: 407–417.

8. WangL, McLeodHL, WeinshilboumRM (2011) Genomics and drug response. N Engl J Med 364: 1144–1153.

9. RodenDM, AltmanRB, BenowitzNL, FlockhartDA, GiacominiKM, et al. (2006) Pharmacogenomics: challenges and opportunities. Ann Intern Med 145: 749–757.

10. Whirl-CarrilloM, McDonaghEM, HebertJM, GongL, SangkuhlK, et al. (2012) Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 92: 414–417.

11. Yan Q (2008) Pharmacogenomics in Drug Discovery and Development: Springer.

12. MegaJL, SimonT, ColletJP, AndersonJL, AntmanEM, et al. (2010) Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 304: 1821–1830.

13. SmithRP, LamET, MarkovaS, YeeSW, AhituvN (2012) Pharmacogene regulatory elements: from discovery to applications. Genome Med 4: 45.

14. SadeeW (2012) The relevance of “missing heritability” in pharmacogenomics. Clin Pharmacol Ther 92: 428–430.

15. CholertonS, DalyAK, IdleJR (1992) The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol Sci 13: 434–439.

16. WrightonSA, VandenBrandenM, RingBJ (1996) The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm 24: 461–473.

17. FlockhartDA, RaeJM (2003) Cytochrome P450 3A pharmacogenetics: the road that needs traveled. Pharmacogenomics J 3: 3–5.

18. KochI, WeilR, WolboldR, BrockmollerJ, HustertE, et al. (2002) Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispos 30: 1108–1114.

19. Martinez-JimenezCP, JoverR, DonatoMT, CastellJV, Gomez-LechonMJ (2007) Transcriptional regulation and expression of CYP3A4 in hepatocytes. Curr Drug Metab 8: 185–194.

20. LambaJK, LinYS, ThummelK, DalyA, WatkinsPB, et al. (2002) Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics 12: 121–132.

21. WangD, GuoY, WrightonSA, CookeGE, SadeeW (2011) Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 11: 274–286.

22. KliewerSA, MooreJT, WadeL, StaudingerJL, WatsonMA, et al. (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92: 73–82.

23. BarwickJL, QuattrochiLC, MillsAS, PotenzaC, TukeyRH, et al. (1996) Trans-species gene transfer for analysis of glucocorticoid-inducible transcriptional activation of transiently expressed human CYP3A4 and rabbit CYP3A6 in primary cultures of adult rat and rabbit hepatocytes. Mol Pharmacol 50: 10–16.

24. GoodwinB, HodgsonE, LiddleC (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56: 1329–1339.

25. MatsumuraK, SaitoT, TakahashiY, OzekiT, KiyotaniK, et al. (2004) Identification of a novel polymorphic enhancer of the human CYP3A4 gene. Mol Pharmacol 65: 326–334.

26. BertilssonG, BerkenstamA, BlomquistP (2001) Functionally conserved xenobiotic responsive enhancer in cytochrome P450 3A7. Biochem Biophys Res Commun 280: 139–144.

27. WangH, FaucetteS, SueyoshiT, MooreR, FergusonS, et al. (2003) A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. J Biol Chem 278: 14146–14152.

28. CuiJY, GunewardenaSS, RockwellCE, KlaassenCD (2010) ChIPing the cistrome of PXR in mouse liver. Nucleic Acids Res 38: 7943–7963.

29. BoergesenM, PedersenTA, GrossB, van HeeringenSJ, HagenbeekD, et al. (2012) Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor alpha in mouse liver reveals extensive sharing of binding sites. Mol Cell Biol 32: 852–867.

30. BlumbergB, SabbaghWJr, JuguilonH, BoladoJJr, van MeterCM, et al. (1998) SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 12: 3195–3205.

31. LehmannJM, McKeeDD, WatsonMA, WillsonTM, MooreJT, et al. (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102: 1016–1023.

32. ViselA, BlowMJ, LiZ, ZhangT, AkiyamaJA, et al. (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457: 854–858.

33. HeintzmanND, HonGC, HawkinsRD, KheradpourP, StarkA, et al. (2009) Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459: 108–112.

34. CreyghtonMP, ChengAW, WelsteadGG, KooistraT, CareyBW, et al. (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc 107: 21931–21936.

35. Rada-IglesiasA, BajpaiR, SwigutT, BrugmannSA, FlynnRA, et al. (2011) A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470: 279–283.

36. BertilssonG, HeidrichJ, SvenssonK, AsmanM, JendebergL, et al. (1998) Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A 95: 12208–12213.

37. RamamoorthyA, LiuY, PhilipsS, DestaZ, LinH, et al. (2013) Regulation of microRNA expression by rifampin in human hepatocytes. Drug Metab Dispos 41: 1763–1768.

38. RiederMJ, ReinerAP, GageBF, NickersonDA, EbyCS, et al. (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352: 2285–2293.

39. AndoY, SakaH, AndoM, SawaT, MuroK, et al. (2000) Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60: 6921–6926.

40. McLeanCY, BristorD, HillerM, ClarkeSL, SchaarBT, et al. (2010) GREAT improves functional interpretation of cis-regulatory regions. Nat 28: 495–501.

41. SchaubMA, BoyleAP, KundajeA, BatzoglouS, SnyderM (2012) Linking disease associations with regulatory information in the human genome. Genome Res 22: 1748–1759.

42. MauranoMT, HumbertR, RynesE, ThurmanRE, HaugenE, et al. (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337: 1190–1195.

43. ErnstJ, KheradpourP, MikkelsenTS, ShoreshN, WardLD, et al. (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473: 43–49.

44. SimonetWS, BucayN, LauerSJ, TaylorJM (1993) A far-downstream hepatocyte-specific control region directs expression of the linked human apolipoprotein E and C-I genes in transgenic mice. J Biol Chem 268: 8221–8229.

45. ChaPC, MushirodaT, TakahashiA, KuboM, MinamiS, et al. (2010) Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Hum Mol Genet 19: 4735–4744.

46. TakeuchiF, McGinnisR, BourgeoisS, BarnesC, ErikssonN, et al. (2009) A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 5: e1000433.

47. TeichertM, EijgelsheimM, RivadeneiraF, UitterlindenAG, van SchaikRH, et al. (2009) A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet 18: 3758–3768.

48. ShuldinerAR, O'ConnellJR, BlidenKP, GandhiA, RyanK, et al. (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302: 849–857.

49. MannervikB (1985) The isoenzymes of glutathione transferase. Adv Enzymol Relat Areas Mol Biol 57: 357–417.

50. ChenG, RamosE, AdeyemoA, ShrinerD, ZhouJ, et al. (2012) UGT1A1 is a major locus influencing bilirubin levels in African Americans. Eur J Hum Genet 20: 463–468.

51. SannaS, BusoneroF, MaschioA, McArdlePF, UsalaG, et al. (2009) Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia. Hum Mol Genet 18: 2711–2718.

52. BielinskiSJ, ChaiHS, PathakJ, TalwalkarJA, LimburgPJ, et al. (2011) Mayo Genome Consortia: a genotype-phenotype resource for genome-wide association studies with an application to the analysis of circulating bilirubin levels. Mayo Clin Proc 86: 606–614.

53. JohnsonAD, KavousiM, SmithAV, ChenMH, DehghanA, et al. (2009) Genome-wide association meta-analysis for total serum bilirubin levels. Hum Mol Genet 18: 2700–2710.

54. StrassburgCP, KalthoffS, EhmerU (2008) Variability and function of family 1 uridine-5′-diphosphate glucuronosyltransferases (UGT1A). Crit Rev Clin Lab Sci 45: 485–530.

55. KroetzDL, AhituvN, BurchardEG, GuoS, SaliA, et al. (2009) Institutional Profile: The University of California Pharmacogenomics Center: at the interface of genomics, biological mechanisms and drug therapy. Pharmacogenomics 10: 1569–1576.

56. RamagopalanSV, HegerA, BerlangaAJ, MaugeriNJ, LincolnMR, et al. (2010) A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res 20: 1352–1360.

57. TewariAK, YardimciGG, ShibataY, SheffieldNC, SongL, et al. (2012) Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity. Genome Biol 13: R88.

58. WelborenWJ, van DrielMA, Janssen-MegensEM, van HeeringenSJ, SweepFC, et al. (2009) ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands. Embo J 28: 1418–1428.

59. ChorleyBN, CampbellMR, WangX, KaracaM, SambandanD, et al. (2012) Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res 40: 7416–7429.

60. NingB, WangC, MorelF, NowellS, RatnasingheDL, et al. (2004) Human glutathione S-transferase A2 polymorphisms: variant expression, distribution in prostate cancer cases/controls and a novel form. Pharmacogenetics 14: 35–44.

61. TetlowN, BoardPG (2004) Functional polymorphism of human glutathione transferase A2. Pharmacogenetics 14: 111–116.

62. GuyCA, HoogendoornB, SmithSK, ColemanS, O'DonovanMC, et al. (2004) Promoter polymorphisms in glutathione-S-transferase genes affect transcription. Pharmacogenetics 14: 45–51.

63. ColesBF, MorelF, RauchC, HuberWW, YangM, et al. (2001) Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. Pharmacogenetics 11: 663–669.

64. ColesB, NowellSA, MacLeodSL, SweeneyC, LangNP, et al. (2001) The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk. Mutat Res 482: 3–10.

65. PavekP, StejskalovaL, KrausovaL, BitmanM, VrzalR, et al. (2012) Rifampicin Does not Significantly Affect the Expression of Small Heterodimer Partner in Primary Human Hepatocytes. Front Pharmacol 3: 1.

66. RanaR, ChenY, FergusonSS, KisslingGE, SurapureddiS, et al. (2010) Hepatocyte nuclear factor 4{alpha} regulates rifampicin-mediated induction of CYP2C genes in primary cultures of human hepatocytes. Drug Metab Dispos 38: 591–599.

67. LivakKJ, SchmittgenTD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408.

68. KimD, PerteaG, TrapnellC, PimentelH, KelleyR, et al. (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14: R36.

69. BreeseMR, LiuY (2013) NGSUtils: a software suite for analyzing and manipulating next-generation sequencing datasets. Bioinformatics 29: 494–496.

70. LoveMI, HuberH, AndersS (2014) Moderated estimation of fold change and dispersion for RNA-Seq data with DESeq2. bioRxiv

71. ZhangY, LiuT, MeyerCA, EeckhouteJ, JohnsonDS, et al. (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9: R137.

72. ZangC, SchonesDE, ZengC, CuiK, ZhaoK, et al. (2009) A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 25: 1952–1958.

73. DaleRK, PedersenBS, QuinlanAR (2011) Pybedtools: a flexible Python library for manipulating genomic datasets and annotations. Bioinformatics 27: 3423–3424.

74. WelterD, MacarthurJ, MoralesJ, BurdettT, HallP, et al. (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42: D1001–1006.

75. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.