Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci


While coronary artery disease (CAD) is due in part to environmental and metabolic factors, about half of the risk is genetically predetermined. Genome-wide association studies in human populations have identified approximately 150 sites in the genome that appear to be associated with CAD. The mechanisms by which mutations in these regions are responsible for predisposition to CAD remain largely unknown. To begin to explore how disease-specific gene sequences and disease gene function promotes pathology, we have mapped the loci and genes that are downstream of the transcription factor TCF21, which is strongly associated with CAD. By identifying genes that are regulated by TCF21 we have been able to link together multiple other CAD associated genes and begin to identify the critical molecular processes that mediate atherosclerosis in the blood vessel wall and contribute to the genesis of ischemic cardiovascular events.


Vyšlo v časopise: Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci. PLoS Genet 11(5): e32767. doi:10.1371/journal.pgen.1005202
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1005202

Souhrn

While coronary artery disease (CAD) is due in part to environmental and metabolic factors, about half of the risk is genetically predetermined. Genome-wide association studies in human populations have identified approximately 150 sites in the genome that appear to be associated with CAD. The mechanisms by which mutations in these regions are responsible for predisposition to CAD remain largely unknown. To begin to explore how disease-specific gene sequences and disease gene function promotes pathology, we have mapped the loci and genes that are downstream of the transcription factor TCF21, which is strongly associated with CAD. By identifying genes that are regulated by TCF21 we have been able to link together multiple other CAD associated genes and begin to identify the critical molecular processes that mediate atherosclerosis in the blood vessel wall and contribute to the genesis of ischemic cardiovascular events.


Zdroje

1. Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes TL, et al. (2012) Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 45: 25–33. doi: 10.1038/ng.2480 23202125

2. Acharya A, Baek ST, Huang G, Eskiocak B, Goetsch S, et al. (2012) The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors. Development 139: 2139–2149. doi: 10.1242/dev.079970 22573622

3. Hidai H, Bardales R, Goodwin R, Quertermous T, Quertermous EE (1998) Cloning of capsulin, a basic helix-loop-helix factor expressed in progenitor cells of the pericardium and the coronary arteries. Mech Dev 73: 33–43. 9545526

4. Lu J, Chang P, Richardson JA, Gan L, Weiler H, et al. (2000) The basic helix-loop-helix transcription factor capsulin controls spleen organogenesis. Proc Natl Acad Sci U S A 97: 9525–9530. 10944221

5. Quaggin SE, Schwartz L, Cui S, Igarashi P, Deimling J, et al. (1999) The basic-helix-loop-helix protein pod1 is critically important for kidney and lung organogenesis. Development 126: 5771–5783. 10572052

6. Braitsch CM, Combs MD, Quaggin SE, Yutzey KE (2012) Pod1/Tcf21 is regulated by retinoic acid signaling and inhibits differentiation of epicardium-derived cells into smooth muscle in the developing heart. Dev Biol 368: 345–357. doi: 10.1016/j.ydbio.2012.06.002 22687751

7. Gomez D, Owens GK (2012) Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc Res 95: 156–164. doi: 10.1093/cvr/cvs115 22406749

8. Landt SG, Marinov GK, Kundaje A, Kheradpour P, Pauli F, et al. (2012) ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia. Genome Res 22: 1813–1831. doi: 10.1101/gr.136184.111 22955991

9. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ (2013) Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods doi: 10.1038/nmeth.2688

10. Derry JMJ, Zhong H, Molony C, MacNeil D, Guhathakurta D, et al. (2010) Identification of Genes and Networks Driving Cardiovascular and Metabolic Phenotypes in a Mouse F2 Intercross. Plos One 5: e14319. doi: 10.1371/journal.pone.0014319 21179467.

11. Emilsson V, Thorleifsson G, Zhang B, Leonardson AS, Zink F, et al. (2008) Genetics of gene expression and its effect on disease. Nature 452: 423–428. doi: 10.1038/nature06758 18344981

12. Fehrmann RS, Jansen RC, Veldink JH, Westra HJ, Arends D, et al. (2011) Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA. PLoS Genet 7: e1002197. doi: 10.1371/journal.pgen.1002197 21829388

13. Greenawalt DM, Dobrin R, Chudin E, Hatoum IJ, Suver C, et al. (2011) A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome Res 21: 1008–1016. doi: 10.1101/gr.112821.110 21602305

14. Nica AC, Parts L, Glass D, Nisbet J, Barrett A, et al. (2011) The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet 7: e1002003. doi: 10.1371/journal.pgen.1002003 21304890

15. Romanoski CE, Che N, Yin F, Mai N, Pouldar D, et al. (2011) Network for activation of human endothelial cells by oxidized phospholipids: a critical role of heme oxygenase 1. Circ Res 109: e27–41. doi: 10.1161/CIRCRESAHA.111.241869 21737788

16. Schadt EE, Molony C, Chudin E, Hao K, Yang X, et al. (2008) Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6: e107. doi: 10.1371/journal.pbio.0060107 18462017

17. Tu ZD, Keller MP, Zhang CS, Rabaglia ME, Greenawalt DM, et al. (2012) Integrative Analysis of a Cross-Loci Regulation Network Identifies App as a Gene Regulating Insulin Secretion from Pancreatic Islets. PLoS genetics 8: e1003107. doi: 10.1371/journal.pgen.1003107 23236292.

18. Wang SS, Schadt EE, Wang H, Wang XP, Ingram-Drake L, et al. (2007) Identification of pathways for atherosclerosis in mice—Integration of quantitative trait locus analysis and global gene expression data. Circulation research 101: E11–E30. 17641228

19. Yang X, Schadt EE, Wang S, Wang H, Arnold AP, et al. (2006) Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Research 16: 995–1004. 16825664

20. Yang X, Peterson L, Thieringer R, Deignan JL, Wang X, et al. (2010) Identification and validation of genes affecting aortic lesions in mice. J Clin Invest 120: 2414–2422. doi: 10.1172/JCI42742 20577049

21. McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, et al. (2010) GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol 28: 495–501. doi: 10.1038/nbt.1630 20436461

22. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, et al. (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38: 576–589. doi: 10.1016/j.molcel.2010.05.004 20513432

23. Machanick P, Bailey TL (2011) MEME-ChIP: motif analysis of large DNA datasets. Bioinformatics 27: 1696–1697. doi: 10.1093/bioinformatics/btr189 21486936

24. Murre C, McCaw PS, Baltimore D (1989) A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56: 777–783. 2493990

25. Reed BD, Charos AE, Szekely AM, Weissman SM, Snyder M (2008) Genome-wide occupancy of SREBP1 and its partners NFY and SP1 reveals novel functional roles and combinatorial regulation of distinct classes of genes. PLoS Genet 4: e1000133. doi: 10.1371/journal.pgen.1000133 18654640

26. Miyagishi M, Nakajima T, Fukamizu A (2000) Molecular characterization of mesoderm-restricted basic helix-loop-helix protein, POD-1/Capsulin. Int J Mol Med 5: 27–31. 10601570

27. Miller CL, Anderson DR, Kundu RK, Raiesdana A, Nurnberg ST, et al. (2013) Disease-Related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of TCF21 Expression at the 6q23.2 Coronary Heart Disease Locus. PLoS Genet 9: e1003652. doi: 10.1371/journal.pgen.1003652 23874238

28. White JT, Zhang B, Cerqueira DM, Tran U, Wessely O (2010) Notch signaling, wt1 and foxc2 are key regulators of the podocyte gene regulatory network in Xenopus. Development 137: 1863–1873. doi: 10.1242/dev.042887 20431116

29. Dimas AS, Deutsch S, Stranger BE, Montgomery SB, Borel C, et al. (2009) Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325: 1246–1250. doi: 10.1126/science.1174148 19644074

30. Nica AC, Montgomery SB, Dimas AS, Stranger BE, Beazley C, et al. (2010) Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet 6: e1000895. doi: 10.1371/journal.pgen.1000895 20369022

31. Stranger BE, Montgomery SB, Dimas AS, Parts L, Stegle O, et al. (2012) Patterns of cis regulatory variation in diverse human populations. PLoS Genet 8: e1002639. doi: 10.1371/journal.pgen.1002639 22532805

32. Montgomery SB, Sammeth M, Gutierrez-Arcelus M, Lach RP, Ingle C, et al. (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464: 773–777. doi: 10.1038/nature08903 20220756

33. Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, et al. (2007) Population genomics of human gene expression. Nat Genet 39: 1217–1224. 17873874

34. Welter D, MacArthur J, Morales J, Burdett T, Hall P, et al. (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42: D1001–1006. doi: 10.1093/nar/gkt1229 24316577

35. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, et al. (2013) STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 41: D808–815. doi: 10.1093/nar/gks1094 23203871

36. Chamley-Campbell JH, Campbell GR, Ross R (1981) Phenotype-dependent response of cultured aortic smooth muscle to serum mitogens. J Cell Biol 89: 379–383. 7251658

37. Zhao B, Li L, Guan KL (2010) Hippo signaling at a glance. Journal of cell science 123: 4001–4006. doi: 10.1242/jcs.069070 21084559

38. Worsley Hunt R, Wasserman WW (2014) Non-targeted transcription factors motifs are a systemic component of ChIP-seq datasets. Genome Biol 15: 412. doi: 10.1186/s13059-014-0412-4 25070602

39. Zhan Y, Kim S, Yasumoto H, Namba M, Miyazaki H, et al. (2002) Effects of dominant-negative c-Jun on platelet-derived growth factor-induced vascular smooth muscle cell proliferation. Arterioscler Thromb Vasc Biol 22: 82–88. 11788465

40. Funato N, Ohyama K, Kuroda T, Nakamura M (2003) Basic helix-loop-helix transcription factor epicardin/capsulin/Pod-1 suppresses differentiation by negative regulation of transcription. J Biol Chem 278: 7486–7493. 12493738

41. Kaplan S, Kaplan ST, Kiris A, Gedikli O (2014) Impact of initial platelet count on baseline angiographic finding and end-points in ST-elevation myocardial infarction referred for primary percutaneous coronary intervention. International journal of clinical and experimental medicine 7: 1064–1070. 24955183

42. Goliasch G, Forster S, El-Hamid F, Sulzgruber P, Meyer N, et al. (2013) Platelet count predicts cardiovascular mortality in very elderly patients with myocardial infarction. European journal of clinical investigation 43: 332–340. doi: 10.1111/eci.12049 23398046

43. Dangas GD, Claessen BE, Mehran R, Xu K, Fahy M, et al. (2012) Development and validation of a stent thrombosis risk score in patients with acute coronary syndromes. JACC Cardiovascular interventions 5: 1097–1105. doi: 10.1016/j.jcin.2012.07.012 23174632

44. Paajanen TA, Oksala NK, Kuukasjarvi P, Karhunen PJ (2010) Short stature is associated with coronary heart disease: a systematic review of the literature and a meta-analysis. Eur Heart J 31: 1802–1809. doi: 10.1093/eurheartj/ehq155 20530501

45. Rosenbush SW, Parker JM (2014) Height and heart disease. Reviews in cardiovascular medicine 15: 102–108. 25051127

46. Emerging Risk Factors C (2012) Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis. International journal of epidemiology 41: 1419–1433. doi: 10.1093/ije/dys086 22825588

47. Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, et al. (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467: 832–838. doi: 10.1038/nature09410 20881960

48. Nelson CP, Hamby SE, Saleheen D, Hopewell JC, Zeng L, et al. (2015) Genetically-Determined Height and Coronary Artery Disease. New England Journal of Medicine In Press.

49. Makinen VP, Civelek M, Meng Q, Zhang B, Zhu J, et al. (2014) Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease. PLoS Genet 10: e1004502. doi: 10.1371/journal.pgen.1004502 25033284

50. Lees CW, Barrett JC, Parkes M, Satsangi J (2011) New IBD genetics: common pathways with other diseases. Gut 60: 1739–1753. doi: 10.1136/gut.2009.199679 21300624

51. Libby P, Ridker PM, Hansson GK, Leducq Transatlantic Network on A (2009) Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 54: 2129–2138. doi: 10.1016/j.jacc.2009.09.009 19942084

52. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760. doi: 10.1093/bioinformatics/btp324 19451168

53. Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26: 841–842. doi: 10.1093/bioinformatics/btq033 20110278

54. Schunkert H, Konig IR, Kathiresan S, Reilly MP, Assimes TL, et al. (2011) Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 43: 333–338. doi: 10.1038/ng.784 21378990

55. Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, et al. (2007) A genome-wide association study of global gene expression. Nature Genetics 39: 1202–1207. 17873877

56. Duan S, Huang RS, Zhang W, Bleibel WK, Roe CA, et al. (2008) Genetic architecture of transcript-level variation in humans. American Journal of Human Genetics 82: 1101–1113. doi: 10.1016/j.ajhg.2008.03.006 18439551

57. Consortium GP, Abecasis GR, Auton A, Brooks LD, DePristo MA, et al. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491: 56–65. doi: 10.1038/nature11632 23128226

58. Consortium IH, Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM, et al. (2010) Integrating common and rare genetic variation in diverse human populations. Nature 467: 52–58. doi: 10.1038/nature09298 20811451

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

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 5
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa