Metastabile Epiallele – beeinflussen epigenetische Varianten das individuelle Adipositasrisiko?

Zusammenfassung

Epigenetische Modifikationen der DNA stellen einen sehr konservierten Regulationsmechanismus bei Pflanzen, Tieren und Menschen dar. Veränderungen beispielsweise der DNA Methylierung können zu der Entwicklung von Tumoren führen und spielen bei der Entstehung von sogenannten Imprinting Erkrankungen eine Rolle. Unklar ist jedoch die Bedeutung dieser Modifikationen für die Entstehung von chronischen Erkrankungen wie beispielsweise Adipositas. Gewebespezifität, genetischer Einfluss und Variabilität der DNA Methylierung stellen eine große Herausforderung für die Untersuchung dieser Zusammenhänge dar. Ergebisse aus epigenom-weiten Assoziationsstudien (EWAS) sowie die Identifikation von sogenannten metastabilen Epiallelen weisen jedoch darauf hin, dass es Unterschiede in der DNA Methylierung gibt, die das individuelle Risiko für die Entwicklung von Adipositas beeinflussen. Es werden zukünftige Studien zeigen, inwieweit Epigenetik im einzelnen von Bedeutung für die Adipositasentwicklung ist und ob dieses Wissen auch therapeutisch von Nutzen sein könnte.

Summary

Epigenetic modifications are highly conserved between plants, animals and humans. Variants, for example DNA methylation, are playing a role for the development of certain types of tumors and imprinting diseases. However, the impact of these modifications on chronic and common dieases like obesity is less clear.

Tissue specificity, genetic impact and variability of DNA methylation are confounding factors, which could lead to difficulties to analyse the relationship between epigenetics and obesity.

Results of epigenome-wide association studies (EWAS) and the identification of socalled metastable epialleles are pointing towards an importance of these epigenetic modifications for the regulation of the individual risk to develop obesity later in life.

Future studies will provide further evidences pertaining to the extend of epigenetic mechanisms in body weight regulation. The knowledge could be beneficial for therapeutic strategies.

Schlüsselwörter

Adipositas - Epigenetik - metastabiles Epiallel

Keywords

Obesity - epigenetics - metastable epiallel

• Literatur

• 1 WHO. World Health Report. 2014
• 2 Farooqi S, O’Rahilly S. Genetics of obesity in humans. Endocr Rev 27: 710-718 2006;
• 3 Stutzmann F. et al. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 57: 2511-2518 2008;
• 4 Kappil M, Wright RO, Sanders AP. Developmental Origins of Common Disease: Epigenetic Contributions to Obesity. Annu Rev Genomics Hum Genet 17: 177-192 2016;
• 5 Loos RJ. The genetics of adiposity. Curr Opin Genet Dev 50: 86-95 2018;
• 6 Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 27: 325-351 1997;
• 7 Haworth CM, Plomin R, Carnell S, Wardle J. Childhood obesity: genetic and environmental overlap with normal-range BMI. Obesity (Silver Spring) 16: 1585-1590 2008;
• 8 Elks CE. et al. Variability in the heritability of body mass index: a systematic review and meta-regression. Front Endocrinol (Lausanne) 03: 29 2012;
• 9 Hebebrand J, Hinney A, Knoll N, Volckmar AL, Scherag A. Molecular genetic aspects of weight regulation. Dtsch Arztebl Int 110: 338-344 2013;
• 10 Eichler EE. et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11: 446-450 2010;
• 11 Birney E, Smith GD, Greally JM. Epigenomewide Association Studies and the Interpretation of Disease -Omics. PLoS Genet 12: e1006105 2016;
• 12 Waddington CH. Organisers and Genes Cambridge University press; 1940
• 13 Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet (Suppl. 33) 245-254 2003;
• 14 Singal R, Ginder GD. DNA methylation. Blood 93: 4059-4070 1999;
• 15 Adalsteinsson BT, Ferguson-Smith AC. Epigenetic control of the genome-lessons from genomic imprinting. Genes (Basel) 05: 635-655 2014;
• 16 Dawson MA. The cancer epigenome: Concepts, challenges, and therapeutic opportunities. Science 355: 1147-1152 2017;
• 17 Bell CG. The Epigenomic Analysis of Human Obesity. Obesity (Silver Spring) 25: 1471-1481 2017;
• 18 Wahl S. et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature 541: 81-86 2017;
• 19 Dick KJ. et al. DNA methylation and body-mass index: a genome-wide analysis. Lancet 383: 1990-1998 2014;
• 20 Voisin S. et al. Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers. Genome Med 07: 103 2015;
• 21 Richmond RC. et al. DNA Methylation and BMI: Investigating Identified Methylation Sites at HIF3A in a Causal Framework. Diabetes 65: 1231-1244 2016;
• 22 Main AM. et al. DNA methylation and gene expression of HIF3A: cross-tissue validation and associations with BMI and insulin resistance. Clin Epigenetics 08: 89 2016;
• 23 Demerath EW. et al. Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci. Hum Mol Genet 24: 4464-4479 2015;
• 24 Willmer M. et al. Surgically induced interpregnancy weight loss and prevalence of overweight and obesity in offspring. PLoS One 08: e82247 2013;
• 25 Mendelson MM. et al. Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach. PLoS Med 14: e1002215 2017;
• 26 van Iterson M, van Zwet EW, Consortium B, Heijmans BT. Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution. Genome Biol 18: 19 2017;
• 27 Michels KB. et al. Recommendations for the design and analysis of epigenome-wide association studies. Nat Methods 10: 949-955 2013;
• 28 Jaffe AE, Irizarry RA. Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol 15: R31 2014;
• 29 Issa JP. Aging and epigenetic drift: a vicious cycle. J Clin Invest 124: 24-29 2014;
• 30 Puccini A. et al. Colorectal cancer: epigenetic alterations and their clinical implications. Biochim Biophys Acta 1868: 439-448 2017;
• 31 Rakyan VK, Blewitt ME, Druker R, Preis JI, Whitelaw E. Metastable epialleles in mammals. Trends Genet 18: 348-351 2002;
• 32 Morgan HD, Sutherland HG, Martin I, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23: 314-318 1999;
• 33 Mills RE, Bennett EA, Iskow RC, Devine SE. Which transposable elements are active in the human genome?. Trends Genet 23: 183-191 2007;
• 34 Dolinoy DC, Das R, Weidman JR, Jirtle RL. Metastable epialleles, imprinting, and the fetal origins of adult diseases. Pediatr Res 61: 30R-37R 2007;
• 35 Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect 114: 567-572 2006;
• 36 Waterland RA, Travisano M, Tahiliani KG. Dietinduced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female. FASEB J 21: 3380-3385 2007;
• 37 Rakyan VK. et al. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci U S A 100: 2538-2543 2003;
• 38 Zeng L. et al. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90: 181-192 1997;
• 39 Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23: 5293-5300 2003;
• 40 Cooney CA, Dave AA, Wolff GL. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr 132: 2393S-2400S 2002;
• 41 Waterland RA. et al. Maternal methyl supplements increase offspring DNA methylation at Axin Fused. Genesis 44: 401-406 2006;
• 42 Rakyan VK, Beck S. Epigenetic variation and inheritance in mammals. Curr Opin Genet Dev 16: 573-577 2006;
• 43 Waterland RA. Epigenetic mechanisms affecting regulation of energy balance: many questions, few answers. Annu Rev Nutr 34: 337-355 2014;
• 44 Rakyan V, Whitelaw E. Transgenerational epigenetic inheritance. Curr Biol 13: R6 2003;
• 45 Waterland RA. et al. Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet 06: e1001252 2010;
• 46 Dominguez-Salas P. et al. DNA methylation potential: dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women. Am J Clin Nutr 97: 1217-1227 2013;
• 47 Moore SE. et al. Season of birth predicts mortality in rural Gambia. Nature 388: 434 1997;
• 48 Dominguez-Salas P. et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun 05: 3746 2014;
• 49 Silver MJ. et al. Independent genomewide screens identify the tumor suppressor VTRNA2–1 as a human epiallele responsive to periconceptional environment. Genome Biol 16: 118 2015;
• 50 Van Baak TE. et al. Epigenetic supersimilarity of monozygotic twin pairs. Genome Biol 19: 2 2018;
• 51 Krude H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19: 155-157 1998;
• 52 Krude H. et al. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4–10. J Clin Endocrinol Metab 88: 4633-4640 2003;
• 53 Farooqi IS. et al. Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55: 2549-2553 2006;
• 54 Kuehnen P. et al. An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity. PLoS Genet 08: e1002543 2012;
• 55 Kuhnen P. et al. Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity. Cell Metab 24: 502-509 2016;
• 56 Kuehnen P, Krude H. Alu elements and human common diseases like obesity. Mob Genet Elements 02: 197-201 2012;