Comprehensive Longitudinal Study of Epigenetic Mutations in Aging

Overview

Journal Clin Epigenetics

Publisher Biomed Central

Specialty Genetics

Date 2019 Dec 11

PMID 31818313

Citations 13

Authors

Yunzhang Wang

Robert Karlsson

Juulia Jylhava

Asa K Hedman

Catarina Almqvist

Ida K Karlsson

Nancy L Pedersen

Malin Almgren

Sara Hagg

Affiliations

Soon will be listed here.

Abstract

Background: The role of DNA methylation in aging has been widely studied. However, epigenetic mutations, here defined as aberrant methylation levels compared to the distribution in a population, are less understood. Hence, we investigated longitudinal accumulation of epigenetic mutations, using 994 blood samples collected at up to five time points from 375 individuals in old ages.

Results: We verified earlier cross-sectional evidence on the increase of epigenetic mutations with age, and identified important contributing factors including sex, CD19+ B cells, genetic background, cancer diagnosis, and technical artifacts. We further classified epigenetic mutations into High/Low Methylation Outliers (HMO/LMO) according to their changes in methylation, and specifically studied methylation sites (CpGs) that were prone to mutate (frequently mutated CpGs). We validated four epigenetically mutated CpGs using pyrosequencing in 93 samples. Furthermore, by using twins, we concluded that the age-related accumulation of epigenetic mutations was not related to genetic factors, hence driven by stochastic or environmental effects.

Conclusions: Here we conducted a comprehensive study of epigenetic mutation and highlighted its important role in aging process and cancer development.

Citing Articles

Reliable detection of stochastic epigenetic mutations and associations with cardiovascular aging.

Markov Y, Levine M, Higgins-Chen A Geroscience. 2024; 46(6):5745-5765.

PMID: 38736015 PMC: 11493905. DOI: 10.1007/s11357-024-01191-3.

Biological Aging Acceleration Due to Environmental Exposures: An Exciting New Direction in Toxicogenomics Research.

Dutta S, Goodrich J, Dolinoy D, Ruden D Genes (Basel). 2024; 15(1).

PMID: 38275598 PMC: 10815440. DOI: 10.3390/genes15010016.

Dynamic patterns of blood lipids and DNA methylation in response to statin therapy.

Qin X, Wang Y, Pedersen N, Tang B, Hagg S Clin Epigenetics. 2022; 14(1):153.

PMID: 36443870 PMC: 9706978. DOI: 10.1186/s13148-022-01375-8.

Additive and Interactive Genetically Contextual Effects of HbA1c on cg19693031 Methylation in Type 2 Diabetes.

Dawes K, Philibert W, Darbro B, Simons R, Philibert R Genes (Basel). 2022; 13(4).

PMID: 35456489 PMC: 9025650. DOI: 10.3390/genes13040683.

Shared genetic and epigenetic changes link aging and cancer.

Zabransky D, Jaffee E, Weeraratna A Trends Cell Biol. 2022; 32(4):338-350.

PMID: 35144882 PMC: 10202213. DOI: 10.1016/j.tcb.2022.01.004.

References

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

Gentilini D, Scala S, Gaudenzi G, Garagnani P, Capri M, Cescon M . Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach. Oncotarget. 2017; 8(26):41890-41902. PMC: 5522036. DOI: 10.18632/oncotarget.17462. View

Wang Y, Karlsson R, Lampa E, Zhang Q, Hedman A, Almgren M . Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins. Epigenetics. 2018; 13(9):975-987. PMC: 6284777. DOI: 10.1080/15592294.2018.1526028. View

Reinius L, Acevedo N, Joerink M, Pershagen G, Dahlen S, Greco D . Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility. PLoS One. 2012; 7(7):e41361. PMC: 3405143. DOI: 10.1371/journal.pone.0041361. View

Bell J, Tsai P, Yang T, Pidsley R, Nisbet J, Glass D . Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet. 2012; 8(4):e1002629. PMC: 3330116. DOI: 10.1371/journal.pgen.1002629. View

Diez-Villanueva A, Mallona I, Peinado M . Wanderer, an interactive viewer to explore DNA methylation and gene expression data in human cancer. Epigenetics Chromatin. 2015; 8:22. PMC: 4480445. DOI: 10.1186/s13072-015-0014-8. View

Ghosh J, Mainigi M, Coutifaris C, Sapienza C . Outlier DNA methylation levels as an indicator of environmental exposure and risk of undesirable birth outcome. Hum Mol Genet. 2015; 25(1):123-9. PMC: 4690496. DOI: 10.1093/hmg/ddv458. View

Fraga M, Ballestar E, Paz M, Ropero S, Setien F, Ballestar M . Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005; 102(30):10604-9. PMC: 1174919. DOI: 10.1073/pnas.0500398102. View

Wang Y, Pedersen N, Hagg S . Implementing a method for studying longitudinal DNA methylation variability in association with age. Epigenetics. 2018; 13(8):866-874. PMC: 6291263. DOI: 10.1080/15592294.2018.1521222. View

10.

Gentilini D, Garagnani P, Pisoni S, Bacalini M, Calzari L, Mari D . Stochastic epigenetic mutations (DNA methylation) increase exponentially in human aging and correlate with X chromosome inactivation skewing in females. Aging (Albany NY). 2015; 7(8):568-78. PMC: 4586102. DOI: 10.18632/aging.100792. View

11.

Auton A, Brooks L, Durbin R, Garrison E, Kang H, Korbel J . A global reference for human genetic variation. Nature. 2015; 526(7571):68-74. PMC: 4750478. DOI: 10.1038/nature15393. View

12.

Zerbino D, Wilder S, Johnson N, Juettemann T, Flicek P . The ensembl regulatory build. Genome Biol. 2015; 16:56. PMC: 4407537. DOI: 10.1186/s13059-015-0621-5. View

13.

Ghosh J, Schultz B, Coutifaris C, Sapienza C . Highly variant DNA methylation in normal tissues identifies a distinct subclass of cancer patients. Adv Cancer Res. 2019; 142:1-22. DOI: 10.1016/bs.acr.2019.01.006. View

14.

Leek J, Johnson W, Parker H, Jaffe A, Storey J . The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012; 28(6):882-3. PMC: 3307112. DOI: 10.1093/bioinformatics/bts034. View

15.

Howie B, Marchini J, Stephens M . Genotype imputation with thousands of genomes. G3 (Bethesda). 2012; 1(6):457-70. PMC: 3276165. DOI: 10.1534/g3.111.001198. View

16.

Houseman E, Accomando W, Koestler D, Christensen B, Marsit C, Nelson H . DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. 2012; 13:86. PMC: 3532182. DOI: 10.1186/1471-2105-13-86. View

17.

Feinberg A, Koldobskiy M, Gondor A . Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016; 17(5):284-99. PMC: 4888057. DOI: 10.1038/nrg.2016.13. View

18.

Teschendorff A, Gao Y, Jones A, Ruebner M, Beckmann M, Wachter D . DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nat Commun. 2016; 7:10478. PMC: 4740178. DOI: 10.1038/ncomms10478. View

19.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

20.

Howie B, Donnelly P, Marchini J . A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009; 5(6):e1000529. PMC: 2689936. DOI: 10.1371/journal.pgen.1000529. View