Stochastic Epigenetic Mutations (DNA Methylation) Increase Exponentially in Human Aging and Correlate with X Chromosome Inactivation Skewing in Females

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2015 Sep 7

PMID 26342808

Citations 42

Authors

Davide Gentilini

Paolo Garagnani

Serena Pisoni

Maria Giulia Bacalini

Luciano Calzari

Daniela Mari

Giovanni Vitale

Claudio Franceschi

Anna Maria Di Blasio

Affiliations

Soon will be listed here.

Abstract

In this study we applied a new analytical strategy to investigate the relations between stochastic epigenetic mutations (SEMs) and aging. We analysed methylation levels through the Infinium HumanMethylation27 and HumanMethylation450 BeadChips in a population of 178 subjects ranging from 3 to 106 years. For each CpG probe, epimutated subjects were identified as the extreme outliers with methylation level exceeding three times interquartile ranges the first quartile (Q1-(3 x IQR)) or the third quartile (Q3+(3 x IQR)). We demonstrated that the number of SEMs was low in childhood and increased exponentially during aging. Using the HUMARA method, skewing of X chromosome inactivation (XCI) was evaluated in heterozygotes women. Multivariate analysis indicated a significant correlation between log(SEMs) and degree of XCI skewing after adjustment for age (β = 0.41; confidence interval: 0.14, 0.68; p-value = 0.0053). The PATH analysis tested the complete model containing the variables: skewing of XCI, age, log(SEMs) and overall CpG methylation. After adjusting for the number of epimutations we failed to confirm the well reported correlation between skewing of XCI and aging. This evidence might suggest that the known correlation between XCI skewing and aging could not be a direct association but mediated by the number of SEMs.

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References

Lengauer C, Kinzler K, Vogelstein B . DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sci U S A. 1997; 94(6):2545-50. PMC: 20125. DOI: 10.1073/pnas.94.6.2545. View

Ong M, Holbrook J . Novel region discovery method for Infinium 450K DNA methylation data reveals changes associated with aging in muscle and neuronal pathways. Aging Cell. 2013; 13(1):142-55. PMC: 4326857. DOI: 10.1111/acel.12159. View

Gentilini D, Mari D, Castaldi D, Remondini D, Ogliari G, Ostan R . Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians' offspring. Age (Dordr). 2012; 35(5):1961-73. PMC: 3776126. DOI: 10.1007/s11357-012-9463-1. View

Hatakeyama C, Anderson C, Beever C, Penaherrera M, Brown C, Robinson W . The dynamics of X-inactivation skewing as women age. Clin Genet. 2004; 66(4):327-32. DOI: 10.1111/j.1399-0004.2004.00310.x. View

Sandovici I, Naumova A, Leppert M, Linares Y, Sapienza C . A longitudinal study of X-inactivation ratio in human females. Hum Genet. 2004; 115(5):387-92. DOI: 10.1007/s00439-004-1177-8. View

Knudsen G, Pedersen J, Klingenberg O, Lygren I, Orstavik K . Increased skewing of X chromosome inactivation with age in both blood and buccal cells. Cytogenet Genome Res. 2007; 116(1-2):24-8. DOI: 10.1159/000097414. View

Garagnani P, Bacalini M, Pirazzini C, Gori D, Giuliani C, Mari D . Methylation of ELOVL2 gene as a new epigenetic marker of age. Aging Cell. 2012; 11(6):1132-4. DOI: 10.1111/acel.12005. View

Medema R, Burgering B . The X factor: skewing X inactivation towards cancer. Cell. 2007; 129(7):1253-4. DOI: 10.1016/j.cell.2007.06.008. View

van Otterdijk S, Mathers J, Strathdee G . Do age-related changes in DNA methylation play a role in the development of age-related diseases?. Biochem Soc Trans. 2013; 41(3):803-7. DOI: 10.1042/BST20120358. View

10.

Horvath S . DNA methylation age of human tissues and cell types. Genome Biol. 2013; 14(10):R115. PMC: 4015143. DOI: 10.1186/gb-2013-14-10-r115. View

11.

Invernizzi P, Miozzo M, Battezzati P, Bianchi I, Grati F, Simoni G . Frequency of monosomy X in women with primary biliary cirrhosis. Lancet. 2004; 363(9408):533-5. DOI: 10.1016/S0140-6736(04)15541-4. View

12.

Kristiansen M, Knudsen G, Maguire P, Margolin S, Pedersen J, Lindblom A . High incidence of skewed X chromosome inactivation in young patients with familial non-BRCA1/BRCA2 breast cancer. J Med Genet. 2005; 42(11):877-80. PMC: 1735952. DOI: 10.1136/jmg.2005.032433. View

13.

Busque L, Paquette Y, Provost S, Roy D, Levine R, Mollica L . Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies. Blood. 2009; 113(15):3472-4. PMC: 4729536. DOI: 10.1182/blood-2008-12-195677. View

14.

Ross S . Diet and DNA methylation interactions in cancer prevention. Ann N Y Acad Sci. 2003; 983:197-207. DOI: 10.1111/j.1749-6632.2003.tb05974.x. View

15.

Brix T, Knudsen G, Kristiansen M, Kyvik K, Orstavik K, Hegedus L . High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endocrinol Metab. 2005; 90(11):5949-53. DOI: 10.1210/jc.2005-1366. View

16.

Rezwan F, Docherty L, Poole R, Lockett G, Arshad S, Holloway J . A statistical method for single sample analysis of HumanMethylation450 array data: genome-wide methylation analysis of patients with imprinting disorders. Clin Epigenetics. 2015; 7:48. PMC: 4410592. DOI: 10.1186/s13148-015-0081-5. View

17.

Bird A . DNA methylation patterns and epigenetic memory. Genes Dev. 2002; 16(1):6-21. DOI: 10.1101/gad.947102. View

18.

Christensen B, Houseman E, Marsit C, Zheng S, Wrensch M, Wiemels J . Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet. 2009; 5(8):e1000602. PMC: 2718614. DOI: 10.1371/journal.pgen.1000602. View

19.

Gentilini D, Castaldi D, Mari D, Monti D, Franceschi C, Di Blasio A . Age-dependent skewing of X chromosome inactivation appears delayed in centenarians' offspring. Is there a role for allelic imbalance in healthy aging and longevity?. Aging Cell. 2012; 11(2):277-83. DOI: 10.1111/j.1474-9726.2012.00790.x. View

20.

Choi J, James S, Link P, McCann S, Hong C, Davis W . Association between global DNA hypomethylation in leukocytes and risk of breast cancer. Carcinogenesis. 2009; 30(11):1889-97. PMC: 2783000. DOI: 10.1093/carcin/bgp143. View