Abstract
Background
This study measured longitudinal DNA methylation dynamics at growth-related genes during childhood, and then tested whether DNA methylation at various stages of childhood was associated with obesity status.
Methods
Using neonatal bloodspot (n = 132) and matched childhood blood samples (n = 65), DNA methylation was quantified at a repetitive element (long interspersed nuclear element-1 (LINE-1)), two imprinted genes (IGF2, H19), and four non-imprinted genes (LEP, PPARA, ESR1, SREBF1) related to growth and adiposity. Logistic regression was used to test whether neonatal bloodspot DNA methylation at target genes was associated with log odds of obesity (Y/N) in children recruited from three age groups—12–24 months old (n = 40), 3–5 years of age (n = 40), and 10–12 years of age (n = 52).
Results
In 3–5 year olds, neonatal bloodspot LINE-1 methylation was negatively associated with obesity (log odds = −0.40, p = 0.04). Across childhood age group in matched blood samples, DNA methylation levels in blood decreased (p < 0.05) at LINE-1, PPARA, ESR1, SREBF1, IGF2, and H19, and increased (p < 0.05) at LEP.
Conclusions
Our results suggest that age-related epigenetic changes occur at growth-related genes in the first decade of life, and that gene-specific neonatal bloodspot DNA methylation may be a useful biomarker of obesity likelihood during childhood.
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References
Hales, C. M., Carroll, M. D., Fryar, C. D. & Ogden C. L. Prevalence of Obesity Among Adults and Youth: United States, 2015-2016. NCHS Data Brief. 288,1–8 (2017).
Dixon, J. B. The effect of obesity on health outcomes. Mol. Cell. Endocrinol. 316, 104–108 (2010).
Loos, R. J. F., . & Janssens, A. C. J. W. Predicting polygenic obesity using genetic information. Cell Metab. 25, 535–543 (2017).
Bernal, A. J. & Jirtle, R. L. Epigenomic disruption: the effects of early developmental exposures. Birth Defects Res. A 88, 938–944 (2010).
Essex, M. J. et al. Epigenetic vestiges of early developmental adversity: childhood stress exposure and DNA methylation in adolescence. Child Dev. 84, 58–75 (2013).
Tellez-Plaza, M. et al. Association of global DNA methylation and global DNA hydroxymethylation with metals and other exposures in human blood DNA samples. Environ. Health Perspect. 122, 946–954 (2014).
Martino, D. et al. Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance. Genome Biol. 14, R42 (2013).
Madrigano, J. et al. Aging and epigenetics: longitudinal changes in gene-specific DNA methylation. Epigenetics 7, 63–70 (2012).
Urdinguio, R. G. et al. Longitudinal study of DNA methylation during the first 5 years of life. J. Transl. Med. 14, 160 (2016).
Horvath, S. et al. Obesity accelerates epigenetic aging of human liver. Proc. Natl Acad. Sci. USA 111, 15538–15543 (2014).
Wahl, S. et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature 541, 81–86 (2016).
Rodić, N., Burns, K. H., Vallot, C., Castoro, R. & Chung, W. Long interspersed element-1 (LINE-1): passenger or driver in human neoplasms? PLoS Genet. 9, e1003402 (2013).
Yang, A. S. et al. A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res. 32, e38 (2004).
Huang, R.-C. et al. DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults. Clin. Epigenet. 4, 21 (2012).
Yoon, M. The role of PPARα in lipid metabolism and obesity: fcusing on the effects of estrogen on PPARα actions. Pharmacol. Res. 60, 151–159 (2009).
Crujeiras, A. B. et al. Leptin resistance in obesity: an epigenetic landscape. Life Sci. 140, 57–63 (2015).
Mauvais-Jarvis, F. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol. Metab. 22, 24–33 (2011).
Ferré, P. & Foufelle, F. SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm. Res. 68, 72–82 (2007).
Acharya, Y., Norton, E. C. & Lumeng, J. C. The effect of financial compensation on willingness to supply a child's blood sample: a Randomized Controlled Trial. Eval. Health Prof. 40, 359–371 (2017).
Center for Health Statistics N. Vital and Health Statistics Series 11, No. 246 (5/2002)—updated 6/30/2010. 2000 CDC Growth Charts for the United States: Methods and Development. https://www.cdc.gov/nchs/data/series/sr_11/sr11_246.pdf (2000).
Centers for Disease Control and Prevention. Defining Childhood Obesity https://www.cdc.gov/obesity/childhood/defining.html (2017).
Virani, S. et al. Delivery type not associated with global methylation at birth. Clin. Epigenet. 4, 8 (2012).
Lesseur, C. et al. Tissue-specific Leptin promoter DNA methylation is associated with maternal and infant perinatal factors. Mol. Cell Endocrinol. 381, 160–167 (2013).
Hoyo, C. et al. Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy. Epigenetics 6, 928–936 (2011).
Adaikalakoteswari, A. et al. Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes. Clin. Epigenet. 7, 14 (2015).
Wang, T. et al. A novel analytical strategy to identify fusion transcripts between repetitive elements and protein coding-exons using RNA-Seq. PLoS ONE 11, e0159028 (2016).
Chao, W. & D’Amore, P. A. IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev. 19, 111–120 (2008).
Tobi, E. W. et al. Prenatal famine and genetic variation are independently and additively associated with DNA methylation at regulatory loci within IGF2/H19. PLoS ONE 7, e37933 (2012).
Hoyo, C. et al. Association of cord blood methylation fractions at imprinted insulin-like growth factor 2 (IGF2), plasma IGF2, and birth weight. Cancer Causes Control 23, 635–645 (2012).
St-Pierre, J. et al. IGF2 DNA methylation is a modulator of newborn’s fetal growth and development. Epigenetics 7, 1125–1132 (2012).
Chung, S., Kim, Y. J., Yang, S. J., Lee, Y. & Lee, M. Nutrigenomic functions of PPARs in obesogenic environments. PPAR Res. 2016, 1–17 (2016).
Heyn, H. et al. Distinct DNA methylomes of newborns and centenarians. Proc. Natl Acad. Sci. USA 109, 10522–10527 (2012).
Alisch, R. S. et al. Age-associated DNA methylation in pediatric populations. Genome Res. 22, 623–632 (2012).
Xu, C.-J. et al. The emerging landscape of dynamic DNA methylation in early childhood. BMC Genom. 18, 25 (2017).
Jones, M. J., Goodman, S. J. & Kobor, M. S. DNA methylation and healthy human aging. Aging Cell 14, 924–932 (2015).
Kaz, A. M. et al. Patterns of DNA methylation in the normal colon vary by anatomical location, gender, and age. Epigenetics 9, 492–502 (2014).
Simpkin, A. J. et al. Longitudinal analysis of DNA methylation associated with birth weight and gestational age. Hum. Mol. Genet. 24, 3752–3763 (2015).
Acevedo, N. et al. Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes. Clin. Epigenet. 7, 34 (2015).
Sjoholm, M. I. L., Dillner, J. & Carlson, J. Assessing quality and functionality of DNA from fresh and archival dried blood spots and recommendations for quality control guidelines. Clin. Chem. 53, 1401–1407 (2007).
Acknowledgements
We acknowledge the Michigan Neonatal Biobank for providing neonatal bloodspots. Data for this study were collected as a part of the Healthy Families Project, funded by the Michigan Momentum Center. The work was supported by the MCubed program at the University of Michigan; the Michigan NIEHS Core Center P30 ES017885; and the T32 ES007062.
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Kochmanski, J., Goodrich, J.M., Peterson, K.E. et al. Neonatal bloodspot DNA methylation patterns are associated with childhood weight status in the Healthy Families Project. Pediatr Res 85, 848–855 (2019). https://doi.org/10.1038/s41390-018-0227-1
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DOI: https://doi.org/10.1038/s41390-018-0227-1
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