The IGF1 P2 promoter is an epigenetic QTL for circulating IGF1 and human growth
详细信息    查看全文
  • 作者：Meriem Ouni (1)
    Yasemin Gunes (1)
    Marie-Pierre Belot (1)
    Anne-Laure Castell (2)
    Delphine Fradin (1)
    Pierre Bougn猫res (1) (2)

    1. Institut National de la Sant茅 et de la Recherche M茅dicale U986     ; Bic锚tre Hospital ; Paris Sud University ; 80 rue du G茅n茅ral Leclerc Le Kremlin-Bic锚tre ; Paris ; 94276 ; France
    2. Department of Pediatric Endocrinology and Diabetes     ; I3E Pole ; Bic锚tre Hospital ; Paris Sud University ; rue du G茅n茅ral Leclerc Le Kremlin-Bic锚tre ; Paris ; 94276 ; France
  • 关键词：QTLepi ; Growth ; Short stature ; Height ; IGF1 ; Epigenetics ; DNA methylation ; t ; DMR
  • 刊名：Clinical Epigenetics
  • 出版年：2015
  • 出版时间：December 2015
  • 年：2015
  • 卷：7
  • 期：1
  • 全文大小：1,716 KB
  • 参考文献：1. Cohen, P, Rogol, AD, Deal, CL, Saenger, P, Reiter, EO, Ross, JL (2007) Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 2008: pp. 4210-7
    2. Rosenfeld, RG (2005) The molecular basis of idiopathic short stature. Growth Horm IGF Res 15: pp. S3-5 CrossRef
    3. Cole, TJ (2003) The secular trend in human physical growth: a biological view. Econ Hum Biol 1: pp. 161-8 CrossRef
    4. Galton, F, Dickson, JDH (1886) Family likeness in stature. Proc R Soc Lond 40: pp. 42-73 CrossRef
    5. Visscher, PM, McEvoy, B, Yang, J (2010) From Galton to GWAS: quantitative genetics of human height. Genet Res 92: pp. 371-9 CrossRef
    6. Hirschhorn, JN, Gajdos, ZKZ (2011) Genome-wide association studies: results from the first few years and potential implications for clinical medicine. Annu Rev Med 62: pp. 11-24 CrossRef
    7. Fisher, RA (1919) XV. - The correlation between relatives on the supposition of Mendelian inheritance. Earth Environ Sci Trans R Soc Edinb 52: pp. 399-433 CrossRef
    8. Silventoinen, K, Sammalisto, S, Perola, M, Boomsma, DI, Cornes, BK, Davis, C (2003) Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res 6: pp. 399-408 CrossRef
    9. Wood, AR, Esko, T, Yang, J, Vedantam, S, Pers, TH, Gustafsson, S (2014) Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 46: pp. 1173-86 CrossRef
    10. Lango Allen, H, Estrada, K, Lettre, G, Berndt, SI, Weedon, MN, Rivadeneira, F (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467: pp. 832-8 CrossRef
    11. Yang, J, Benyamin, B, McEvoy, BP, Gordon, S, Henders, AK, Nyholt, DR (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42: pp. 565-9 CrossRef
    12. Murrell, A, Rakyan, VK, Beck, S (2005) From genome to epigenome. Hum Mol Genet 14: pp. R3-10 CrossRef
    13. Johannes, F, Colot, V, Jansen, RC (2008) Epigenome dynamics: a quantitative genetics perspective. Nat Rev Genet 9: pp. 883-90 CrossRef
    14. Rakyan, VK, Down, TA, Balding, DJ, Beck, S (2011) Epigenome-wide association studies for common human diseases. Nat Rev Genet 12: pp. 529-41 CrossRef
    15. Woods, KA, Camacho-H眉bner, C, Savage, MO, Clark, AJ (1996) Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 335: pp. 1363-7 CrossRef
    16. Lupu, F, Terwilliger, JD, Lee, K, Segre, GV, Efstratiadis, A (2001) Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 229: pp. 141-62 CrossRef
    17. Rogers, I, Metcalfe, C, Gunnell, D, Emmett, P, Dunger, D, Holly, J (2006) Insulin-like growth factor-I and growth in height, leg length, and trunk length between ages 5 and 10 years. J Clin Endocrinol Metab 91: pp. 2514-9 CrossRef
    18. Cohen, P (2006) Controversy in clinical endocrinology: problems with reclassification of insulin-like growth factor I production and action disorders. J Clin Endocrinol Metab 91: pp. 4235-6 CrossRef
    19. Frayling, TM, Hattersley, AT, McCarthy, A, Holly, J, Mitchell, SMS, Gloyn, AL (2002) A putative functional polymorphism in the IGF-I gene association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in U.K. Populations. Diabetes 51: pp. 2313-6 CrossRef
    20. Lettre, G, Butler, JL, Ardlie, KG, Hirschhorn, JN (2007) Common genetic variation in eight genes of the GH/IGF1 axis does not contribute to adult height variation. Hum Genet 122: pp. 129-39 CrossRef
    21. Kim, J-J, Lee, H-I, Park, T, Kim, K, Lee, J-E, Cho, NH (2009) Identification of 15 loci influencing height in a Korean population. J Hum Genet 55: pp. 27-31 CrossRef
    22. Okada, Y, Kamatani, Y, Takahashi, A, Matsuda, K, Hosono, N, Ohmiya, H (2010) A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. Hum Mol Genet 19: pp. 2303-12 CrossRef
    23. Harrela, M, Koistinen, H, Kaprio, J, Lehtovirta, M, Tuomilehto, J, Eriksson, J (1996) Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3. J Clin Invest 98: pp. 2612-5 CrossRef
    24. Kao, PC, Matheny, AP, Lang, CA (1994) Insulin-like growth factor-I comparisons in healthy twin children. J Clin Endocrinol Metab 78: pp. 310-2
    25. Verhaeghe, J, Loos, R, Vlietinck, R, Herck, E, Bree, R, DSchutter, AM (1996) C-peptide, insulin-like growth factors I and II, and insulin-like growth factor binding protein-1 in cord serum of twins: genetic versus environmental regulation. Am J Obstet Gynecol 175: pp. 1180-8 CrossRef
    26. Palles, C, Johnson, N, Coupland, B, Taylor, C, Carvajal, J, Holly, J (2008) Identification of genetic variants that influence circulating IGF1 levels: a targeted search strategy. Hum Mol Genet 17: pp. 1457-64 CrossRef
    27. Al-Zahrani, A, Sandhu, MS, Luben, RN, Thompson, D, Baynes, C, Pooley, KA (2006) IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet 15: pp. 1-10 CrossRef
    28. Wong, H-L, DeLellis, K, Probst-Hensch, N, Koh, W-P, Berg, DVD, Lee, H-P (2005) A new single nucleotide polymorphism in the insulin-like growth factor I regulatory region associates with colorectal cancer risk in Singapore Chinese. Cancer Epidemiol Biomarkers Prev 14: pp. 144-51
    29. Ester, WA, Hokken-Koelega, ACS (2008) Polymorphisms in the IGF1 and IGF1R genes and children born small for gestational age: results of large population studies. Best Pract Res Clin Endocrinol Metab 22: pp. 415-31 CrossRef
    30. Vaessen, N, Janssen, JA, Heutink, P, Hofman, A, Lamberts, SWJ, Oostra, BA (2002) Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight. Lancet 359: pp. 1036-7 CrossRef
    31. Rotwein, P (2012) Mapping the growth hormone - Stat5b - IGF-I transcriptional circuit. Trends Endocrinol Metab 23: pp. 186-93 CrossRef
    32. Bock, C, Walter, J, Paulsen, M, Lengauer, T (2008) Inter-individual variation of DNA methylation and its implications for large-scale epigenome mapping. Nucleic Acids Res 36: pp. e55 CrossRef
    33. Kuroda, A, Rauch, TA, Todorov, I, Ku, HT, Al-Abdullah, IH, Kandeel, F (2009) Insulin gene expression is regulated by DNA methylation. PLoS ONE 4: pp. e6953 CrossRef
    34. Murgatroyd, C, Patchev, AV, Wu, Y, Micale, V, Bockm眉hl, Y, Fischer, D (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12: pp. 1559-66 CrossRef
    35. Yang, H, Adamo, ML, Koval, AP, McGuinness, MC, Ben-Hur, H, Yang, Y (1995) Alternative leader sequences in insulin-like growth factor I mRNAs modulate translational efficiency and encode multiple signal peptides. Mol Endocrinol 9: pp. 1380-95
    36. Adamo, ML, Ben-Hur, H, Roberts, CT, LeRoith, D (1991) Regulation of start site usage in the leader exons of the rat insulin-like growth factor-I gene by development, fasting, and diabetes. Mol Endocrinol 5: pp. 1677-86 CrossRef
    37. Oberbauer, AM (2013) The regulation of IGF-1 gene transcription and splicing during development and aging. Front Endocrinol 4: pp. 39 CrossRef
    38. Weedon, MN, Lettre, G, Freathy, RM, Lindgren, CM, Voight, BF, Perry, JRB (2007) A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet 39: pp. 1245-50 CrossRef
    39. Sanna, S, Jackson, AU, Nagaraja, R, Willer, CJ, Chen, W-M, Bonnycastle, LL (2008) Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40: pp. 198-203 CrossRef
    40. Weedon, MN, Lango, H, Lindgren, CM, Wallace, C, Evans, DM, Mangino, M (2008) Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 40: pp. 575-83 CrossRef
    41. Bogin, B (2013) Secular changes in childhood, adolescent and adult stature. Nestl茅 Nutr Inst Workshop Ser 71: pp. 115-26 CrossRef
    42. Clemmons, DR, Underwood, LE (1991) Nutritional regulation of IGF-I and IGF binding proteins. Annu Rev Nutr 11: pp. 393-412 CrossRef
    43. Bird, A (2011) Putting the DNA back into DNA methylation. Nat Genet 43: pp. 1050-1 CrossRef
    44. Knight, JC (2004) Allele-specific gene expression uncovered. Trends Genet TIG 20: pp. 113-6 CrossRef
    45. Meaburn, EL, Schalkwyk, LC, Mill, J (2010) Allele-specific methylation in the human genome: implications for genetic studies of complex disease. Epigenetics 5: pp. 578-82 CrossRef
    46. Fradin, D, Fur, S, Mille, C, Naoui, N, Groves, C, Zelenika, D (2012) Association of the CpG methylation pattern of the proximal insulin gene promoter with type 1 diabetes. PLoS ONE 7: pp. e36278 CrossRef
    47. Richards, EJ (2008) Population epigenetics. Curr Opin Genet Dev 18: pp. 221-6 CrossRef
    48. Bell, JT, Pai, AA, Pickrell, JK, Gaffney, DJ, Pique-Regi, R, Degner, JF (2011) DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol 12: pp. R10 CrossRef
    49. Fraga, MF, Ballestar, E, Paz, MF, Ropero, S, Setien, F, Ballestar, ML (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102: pp. 10604-9 CrossRef
    50. Kaminsky, ZA, Tang, T, Wang, S-C, Ptak, C, Oh, GHT, Wong, AHC (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41: pp. 240-5 CrossRef
    51. Petronis, A (2006) Epigenetics and twins: three variations on the theme. Trends Genet TIG 22: pp. 347-50 CrossRef
    52. Yakar, S, Pennisi, P, Wu, Y, Zhao, H, LeRoith, D Clinical relevance of systemic and local IGF-I. In: Cianfarani, S, Clemmons, DR, Savage, MO eds. (2005) Endocrine Development. KARGER, Basel, pp. 11-6
    53. Liu, JL, Yakar, S, LeRoith, D (2000) Conditional knockout of mouse insulin-like growth factor-1 gene using the Cre/loxP system. Proc Soc Exp Biol Med 223: pp. 344-51 CrossRef
    54. Feinberg, AP, Irizarry, RA, Fradin, D, Aryee, MJ, Murakami, P, Aspelund, T (2010) Personalized epigenomic signatures that are stable over time and covary with body mass index. Sci Transl Med 2: pp. 49ra67 CrossRef
    55. Talens, RP, Boomsma, DI, Tobi, EW, Kremer, D, Jukema, JW, Willemsen, G (2010) Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J 24: pp. 3135-44 CrossRef
    56. Mill, J, Heijmans, BT (2013) From promises to practical strategies in epigenetic epidemiology. Nat Rev Genet 14: pp. 585-94 CrossRef
    57. Wu, H-C, Delgado-Cruzata, L, Flom, JD, Kappil, M, Ferris, JS, Liao, Y (2011) Global methylation profiles in DNA from different blood cell types. Epigenetics 6: pp. 76-85 CrossRef
    58. Xie, W, Schultz, MD, Lister, R, Hou, Z, Rajagopal, N, Ray, P (2013) Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell 153: pp. 1134-48 CrossRef
    59. Takai, D, Jones, PA (2002) Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 99: pp. 3740-5 CrossRef
    60. Han, H, Cortez, CC, Yang, X, Nichols, PW, Jones, PA, Liang, G (2011) DNA methylation directly silences genes with non-CpG island promoters and establishes a nucleosome occupied promoter. Hum Mol Genet 20: pp. 4299-310 CrossRef
    61. Eckhardt, F, Lewin, J, Cortese, R, Rakyan, VK, Attwood, J, Burger, M (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38: pp. 1378-85 CrossRef
    62. Weber, M, Hellmann, I, Stadler, MB, Ramos, L, P盲盲bo, S, Rebhan, M (2007) Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39: pp. 457-66 CrossRef
    63. Gal-Yam, EN, Egger, G, Iniguez, L, Holster, H, Einarsson, S, Zhang, X (2008) Frequent switching of polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc Natl Acad Sci U S A 105: pp. 12979-84 CrossRef
    64. Klug, M, Rehli, M (2006) Functional analysis of promoter CpG methylation using a CpG-free luciferase reporter vector. Epigenetics 1: pp. 127-30 CrossRef
    65. Varco-Merth, B, Mirza, K, Alzhanov, DT, Chia, DJ, Rotwein, P (2012) Biochemical characterization of diverse Stat5b-binding enhancers that mediate growth hormone-activated insulin-like growth factor-I gene transcription. PLoS ONE 7: pp. e50278 CrossRef
    66. Chia, DJ, Young, JJ, Mertens, AR, Rotwein, P (2010) Distinct alterations in chromatin organization of the two IGF-I promoters precede growth hormone-induced activation of IGF-I gene transcription. Mol Endocrinol 24: pp. 779-89 CrossRef
    67. Chia, DJ, Rotwein, P (2010) Defining the epigenetic actions of growth hormone: acute chromatin changes accompany GH-activated gene transcription. Mol Endocrinol 24: pp. 2038-49 CrossRef
    68. Slatkin, M (2009) Epigenetic inheritance and the missing heritability problem. Genetics 182: pp. 845-50 CrossRef
    69. Manolio, TA, Collins, FS, Cox, NJ, Goldstein, DB, Hindorff, LA, Hunter, DJ (2009) Finding the missing heritability of complex diseases. Nature 461: pp. 747-53 CrossRef
    70. Atchley, WR, Zhu, J (1997) Developmental quantitative genetics, conditional epigenetic variability and growth in mice. Genetics 147: pp. 765-76
    71. Santos, C, Essioux, L, Teinturier, C, Tauber, M, Goffin, V, Bougn猫res, P (2004) A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet 36: pp. 720-4 CrossRef
    72. Alberti, C, Chevenne, D, Mercat, I, Josserand, E, Armoogum-Boizeau, P, Tichet, J (2011) Serum concentrations of insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3), IGF-1/IGFBP-3 ratio, and markers of bone turnover: reference values for French children and adolescents and z-score comparability with other references. Clin Chem 57: pp. 1424-35 CrossRef
    73. Jansen, E, Steenbergh, PH, LeRoith, D, Roberts, CT, Sussenbach, JS (1991) Identification of multiple transcription start sites in the human insulin-like growth factor-I gene. Mol Cell Endocrinol 78: pp. 115-25 CrossRef
    74. Tost, J, Gut, IG (2007) DNA methylation analysis by pyrosequencing. Nat Protoc 2: pp. 2265-75 CrossRef
    75. Cleveland, RJ, Gammon, MD, Edmiston, SN, Teitelbaum, SL, Britton, JA, Terry, MB (2006) IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the Long Island Breast Cancer Study Project. Carcinogenesis 27: pp. 758-65 CrossRef
    76. Arends, N, Johnston, L, Hokken-Koelega, A, Duijn, C, Ridder, M, Savage, M (2002) Polymorphism in the IGF-I gene: clinical relevance for short children born small for gestational age (SGA). J Clin Endocrinol Metab 87: pp. 2720 CrossRef
  • 刊物主题：Human Genetics; Gene Function;
  • 出版者：BioMed Central
  • ISSN：1868-7083
文摘
Background Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Indeed, genome-wide association study (GWAS) have revealed hundreds of variants that contribute to the variability of height but could explain only a limited part of it, and no single variant accounts for more than 0.3% of height variance. At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits, an emerging challenge in humans, has not been attempted for height. Since insulin-like growth factor 1 (IGF1) controls postnatal growth, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene is a potential epigenetic contributor to the individual variation in circulating IGF1 and stature in growing children. Results Child height was closely correlated with serum IGF1. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. The highest association was for CG-137 methylation, which contributed 13% to the variance of height and 10% to serum IGF1. CG methylation (studied in children undergoing surgery) was approximately 50% lower in liver and growth plates, indicating that the IGF1 promoters are tissue-differentially methylated regions (t-DMR). CG methylation was inversely correlated with the transcriptional activity of the P2 promoter in mononuclear blood cells and in transfection experiments, suggesting that the observed association of methylation with the studied traits reflects true biological causality. Conclusions Our observations introduce epigenetics among the individual determinants of child growth and serum IGF1. The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTLepi) reported in humans. The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature.

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址：北京市海淀区学院路29号 邮编：100083

电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700