Regulatory interaction between the ZPBP2-ORMDL3/Zpbp2-Ormdl3 region and the circadian clock

Autoři: Matthew L. Chang aff001;  Sanny Moussette aff001;  Enrique Gamero-Estevez aff002;  José Héctor Gálvez aff003;  Victoria Chiwara aff002;  Indra R. Gupta aff001;  Aimee K. Ryan aff001;  Anna K. Naumova aff001
Působiště autorů: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada aff001;  Department of Human Genetics, McGill University, Montreal, Quebec, Canada aff002;  Canadian Centre for Computational Genomics, Montreal, Quebec, Canada aff003;  Department of Paediatrics, McGill University, Montreal, Quebec, Canada aff004;  Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada aff005
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223212


Genome-wide association study (GWAS) loci for several immunity-mediated diseases (early onset asthma, inflammatory bowel disease (IBD), primary biliary cholangitis, and rheumatoid arthritis) map to chromosomal region 17q12-q21. The predominant view is that association between 17q12-q21 alleles and increased risk of developing asthma or IBD is due to regulatory variants. ORM sphingolipid biosynthesis regulator (ORMDL3) residing in this region is the most promising gene candidate for explaining association with disease. However, the relationship between 17q12-q21 alleles and disease is complex suggesting contributions from other factors, such as trans-acting genetic and environmental modifiers or circadian rhythms. Circadian rhythms regulate expression levels of thousands of genes and their dysregulation is implicated in the etiology of several common chronic inflammatory diseases. However, their role in the regulation of the 17q12-q21 genes has not been investigated. Moreover, the core clock gene nuclear receptor subfamily 1, group D, member 1 (NR1D1) resides about 200 kb distal to the GWAS region. We hypothesized that circadian rhythms influenced gene expression levels in 17q12-q21 region and conversely, regulatory elements in this region influenced transcription of the core clock gene NR1D1 in cis. To test these hypotheses, we examined the diurnal expression profiles of zona pellucida binding protein 2 (ZPBP2/Zpbp2), gasdermin B (GSDMB), and ORMDL3/Ormdl3 in human and mouse tissues and analyzed the impact of genetic variation in the ZPBP2/Zpbp2 region on NR1D1/Nr1d1 expression. We found that Ormdl3 and Zpbp2 were controlled by the circadian clock in a tissue-specific fashion. We also report that deletion of the Zpbp2 region altered the expression profile of Nr1d1 in lungs and ileum in a time-dependent manner. In liver, the deletion was associated with enhanced expression of Ormdl3. We provide the first evidence that disease-associated genes Zpbp2 and Ormdl3 are regulated by circadian rhythms and the Zpbp2 region influences expression of the core clock gene Nr1d1.

Klíčová slova:

Asthma – Circadian rhythms – Gene expression – Gene regulation – Ileum – Transcriptional control – Circadian oscillators – Genetic oscillators


1. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007;448(7152):470–3. doi: 10.1038/nature06014 17611496

2. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363(13):1211–21. doi: 10.1056/NEJMoa0906312 20860503

3. Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J, Han B, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016;48(5):510–8. doi: 10.1038/ng.3528 26974007

4. Qiu F, Tang R, Zuo X, Shi X, Wei Y, Zheng X, et al. A genome-wide association study identifies six novel risk loci for primary biliary cholangitis. Nature communications. 2017;8:14828. doi: 10.1038/ncomms14828 28425483

5. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010;42(6):508–14. doi: 10.1038/ng.582 20453842

6. Kurreeman FA, Stahl EA, Okada Y, Liao K, Diogo D, Raychaudhuri S, et al. Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12. Am J Hum Genet. 2012;90(3):524–32. doi: 10.1016/j.ajhg.2012.01.010 22365150

7. Laufer VA, Tiwari HK, Reynolds RJ, Danila MI, Wang J, Edberg JC, et al. Genetic Influences on Susceptibility to Rheumatoid Arthritis in African-Americans. Hum Mol Genet. 2019, 28(5):858–874. doi: 10.1093/hmg/ddy395 30423114

8. Solovieff N, Cotsapas C, Lee PH, Purcell SM, Smoller JW. Pleiotropy in complex traits: challenges and strategies. Nature reviews Genetics. 2013;14(7):483–95. doi: 10.1038/nrg3461 23752797

9. Ge B, Pokholok DK, Kwan T, Grundberg E, Morcos L, Verlaan DJ, et al. Global patterns of cis variation in human cells revealed by high-density allelic expression analysis. Nat Genet. 2009;41(11):1216–22. doi: 10.1038/ng.473 19838192

10. Verlaan DJ, Berlivet S, Hunninghake GM, Madore AM, Lariviere M, Moussette S, et al. Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet. 2009;85(3):377–93. doi: 10.1016/j.ajhg.2009.08.007 19732864

11. Berlivet S, Moussette S, Ouimet M, Verlaan DJ, Koka V, Al Tuwaijri A, et al. Interaction between genetic and epigenetic variation defines gene expression patterns at the asthma-associated locus 17q12-q21 in lymphoblastoid cell lines. Hum Genet. 2012;131(7):1161–71. doi: 10.1007/s00439-012-1142-x 22271045

12. Moussette S, Al Tuwaijri A, Kohan-Ghadr HR, Elzein S, Farias R, Berube J, et al. Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. PLoS One. 2017;12(2):e0172707. doi: 10.1371/journal.pone.0172707 28241063

13. Schmiedel BJ, Seumois G, Samaniego-Castruita D, Cayford J, Schulten V, Chavez L, et al. 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells. Nature communications. 2016;7:13426. doi: 10.1038/ncomms13426 27848966

14. Worgall TS, Veerappan A, Sung B, Kim BI, Weiner E, Bholah R, et al. Impaired sphingolipid synthesis in the respiratory tract induces airway hyperreactivity. Science translational medicine. 2013;5(186):186ra67. doi: 10.1126/scitranslmed.3005765 23698380

15. Espaillat MP, Kew RR, Obeid LM. Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. Advances in biological regulation. 2017;63:140–55. doi: 10.1016/j.jbior.2016.11.001 27866974

16. Zhakupova A, Debeuf N, Krols M, Toussaint W, Vanhoutte L, Alecu I, et al. ORMDL3 expression levels have no influence on the activity of serine palmitoyltransferase. FASEB J. 2016;30(12):4289–300. doi: 10.1096/fj.201600639R 27645259

17. Kelly RS, Chawes BL, Blighe K, Virkud YV, Croteau-Chonka DC, McGeachie MJ, et al. An Integrative Transcriptomic and Metabolomic Study of Lung Function in Children With Asthma. Chest. 2018;154(2):335–48. doi: 10.1016/j.chest.2018.05.038 29908154

18. Siow D, Sunkara M, Dunn TM, Morris AJ, Wattenberg B. ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis. Journal of lipid research. 2015;56(4):898–908. doi: 10.1194/jlr.M057539 25691431

19. Miller M, Rosenthal P, Beppu A, Mueller JL, Hoffman HM, Tam AB, et al. ORMDL3 Transgenic Mice Have Increased Airway Remodeling and Airway Responsiveness Characteristic of Asthma. J Immunol. 2014;192(8):3475–87. doi: 10.4049/jimmunol.1303047 24623133

20. Löser S, Gregory LG, Zhang Y, Schaefer K, Walker SA, Buckley J, et al. Pulmonary ORMDL3 is critical for induction of Alternaria induced allergic airways disease. J Allergy Clin Immunol. 2017, 139(5):1496–1507. doi: 10.1016/j.jaci.2016.07.033 27623174

21. Miller M, Tam AB, Mueller JL, Rosenthal P, Beppu A, Gordillo R, et al. Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate. J Immunol. 2017;198(8):3017–22. doi: 10.4049/jimmunol.1601848 28275141

22. Debeuf N, Zhakupova A, Steiner R, Van Gassen S, Deswarte K, Fayazpour F, et al. The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice. J Allergy Clin Immunol. 2019 (in press).

23. Bass J, Takahashi JS. Circadian integration of metabolism and energetics. Science. 2010;330(6009):1349–54. doi: 10.1126/science.1195027 21127246

24. Labrecque N, Cermakian N. Circadian Clocks in the Immune System. Journal of biological rhythms. 2015;30(4):277–90. doi: 10.1177/0748730415577723 25900041

25. Sundar IK, Yao H, Sellix MT, Rahman I. Circadian clock-coupled lung cellular and molecular functions in chronic airway diseases. American journal of respiratory cell and molecular biology. 2015;53(3):285–90. doi: 10.1165/rcmb.2014-0476TR 25938935

26. Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, et al. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell. 2002;110(2):251–60. doi: 10.1016/s0092-8674(02)00825-5 12150932

27. Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science. 2011;331(6022):1315–9. doi: 10.1126/science.1198125 21393543

28. He B, Chen C, Teng L, Tan K. Global view of enhancer-promoter interactome in human cells. Proc Natl Acad Sci U S A. 2014;111(21):E2191–9. doi: 10.1073/pnas.1320308111 24821768

29. Kanagaratham C, Chiwara V, Ho B, Moussette S, Youssef M, Venuto D, et al. Loss of the zona pellucida-binding protein 2 (Zpbp2) gene in mice impacts airway hypersensitivity and lung lipid metabolism in a sex-dependent fashion. Mamm Genome. 2018;29(3–4):281–98. doi: 10.1007/s00335-018-9743-x 29536159

30. Lin YN, Roy A, Yan W, Burns KH, Matzuk MM. Loss of zona pellucida binding proteins in the acrosomal matrix disrupts acrosome biogenesis and sperm morphogenesis. Mol Cell Biol. 2007;27(19):6794–805. doi: 10.1128/MCB.01029-07 17664285

31. Bourgey M, Dali R, Eveleigh R, Chen KC, Letourneau L, Fillon J, et al. GenPipes: an open-source framework for distributed and scalable genomic analyses. GigaScience. 2019;8(6).

32. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. doi: 10.1093/bioinformatics/bts635 23104886

33. Anders S, Pyl PT, Huber W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–9. doi: 10.1093/bioinformatics/btu638 25260700

34. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40. doi: 10.1093/bioinformatics/btp616 19910308

35. Anders S, Huber W. Differential expression analysis for sequence count data. Genome Biol. 2010;11(10):R106. doi: 10.1186/gb-2010-11-10-r106 20979621

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

37. Christou S, Wehrens SMT, Isherwood C, Moller-Levet CS, Wu H, Revell VL, et al. Circadian regulation in human white adipose tissue revealed by transcriptome and metabolic network analysis. Scientific reports. 2019;9(1):2641. doi: 10.1038/s41598-019-39668-3 30804433

38. Wu G, Ruben MD, Schmidt RE, Francey LJ, Smith DF, Anafi RC, et al. Population-level rhythms in human skin with implications for circadian medicine. Proc Natl Acad Sci U S A. 2018;115(48):12313–8. doi: 10.1073/pnas.1809442115 30377266

39. Kervezee L, Cuesta M, Cermakian N, Boivin DB. Simulated night shift work induces circadian misalignment of the human peripheral blood mononuclear cell transcriptome. Proc Natl Acad Sci U S A. 2018;115(21):5540–5. doi: 10.1073/pnas.1720719115 29735673

40. Archer SN, Laing EE, Moller-Levet CS, van der Veen DR, Bucca G, Lazar AS, et al. Mistimed sleep disrupts circadian regulation of the human transcriptome. Proc Natl Acad Sci U S A. 2014;111(6):E682–91. doi: 10.1073/pnas.1316335111 24449876

41. Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci U S A. 2014;111(45):16219–24. doi: 10.1073/pnas.1408886111 25349387

42. Eckel-Mahan KL, Patel VR, de Mateo S, Orozco-Solis R, Ceglia NJ, Sahar S, et al. Reprogramming of the circadian clock by nutritional challenge. Cell. 2013;155(7):1464–78. doi: 10.1016/j.cell.2013.11.034 24360271

43. Hoogerwerf WA, Sinha M, Conesa A, Luxon BA, Shahinian VB, Cornelissen G, et al. Transcriptional profiling of mRNA expression in the mouse distal colon. Gastroenterology. 2008;135(6):2019–29. doi: 10.1053/j.gastro.2008.08.048 18848557

44. Cohen J. A power primer. Psychological bulletin. 1992;112(1):155–9. doi: 10.1037//0033-2909.112.1.155 19565683

45. Zhang Y, Fang B, Emmett MJ, Damle M, Sun Z, Feng D, et al. GENE REGULATION. Discrete functions of nuclear receptor Rev-erbalpha couple metabolism to the clock. Science. 2015;348(6242):1488–92. doi: 10.1126/science.aab3021 26044300

46. Gibbs JE, Blaikley J, Beesley S, Matthews L, Simpson KD, Boyce SH, et al. The nuclear receptor REV-ERBalpha mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc Natl Acad Sci U S A. 2012;109(2):582–7. doi: 10.1073/pnas.1106750109 22184247

47. Wang S, Lin Y, Yuan X, Li F, Guo L, Wu B. REV-ERBalpha integrates colon clock with experimental colitis through regulation of NF-kappaB/NLRP3 axis. Nature communications. 2018;9(1):4246. doi: 10.1038/s41467-018-06568-5 30315268

48. Xu Y, Guo W, Li P, Zhang Y, Zhao M, Fan Z, et al. Long-Range Chromosome Interactions Mediated by Cohesin Shape Circadian Gene Expression. PLoS Genet. 2016;12(5):e1005992. doi: 10.1371/journal.pgen.1005992 27135601

49. Koike N, Yoo SH, Huang HC, Kumar V, Lee C, Kim TK, et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science. 2012;338(6105):349–54. doi: 10.1126/science.1226339 22936566

50. Partch CL, Green CB, Takahashi JS. Molecular architecture of the mammalian circadian clock. Trends in cell biology. 2014;24(2):90–9. doi: 10.1016/j.tcb.2013.07.002 23916625

51. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348(6235):648–60. doi: 10.1126/science.1262110 25954001

52. Naumova AK, Al Tuwaijri A, Morin A, Vaillancout VT, Madore AM, Berlivet S, et al. Sex- and age-dependent DNA methylation at the 17q12-q21 locus associated with childhood asthma. Hum Genet. 2013;132(7):811–22. doi: 10.1007/s00439-013-1298-z 23546690

53. Al Tuwaijri A, Gagne-Ouellet V, Madore AM, Laprise C, Naumova AK. Local genotype influences DNA methylation at two asthma-associated regions, 5q31 and 17q21, in a founder effect population. Journal of medical genetics. 2016;53(4):232–41. doi: 10.1136/jmedgenet-2015-103313 26671913

54. Stein MM, Thompson EE, Schoettler N, Helling BA, Magnaye KM, Stanhope C, et al. A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle. J Allergy Clin Immunol. 2018, 142(3):749–764. doi: 10.1016/j.jaci.2017.12.974 29307657

Článek vyšel v časopise


2019 Číslo 9

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…

Kurzy Doporučená témata