Early postnatal overnutrition accelerates aging-associated epigenetic drift in pancreatic islets

Authors: LI, GE - Children'S Nutrition Research Center (CNRC); PETKOVA, TIHOMIRA - Children'S Nutrition Research Center (CNRC); LARITSKY, ELEONORA - Children'S Nutrition Research Center (CNRC); KESSLER, NOAH - Children'S Nutrition Research Center (CNRC); BAKER, MARIA - Children'S Nutrition Research Center (CNRC); ZHU, SHAOYU - Children'S Nutrition Research Center (CNRC); WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)

Submitted to: Environmental Epigenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/16/2019
Publication Date: 8/25/2019
Citation: Li, G., Petkova, T.D., Laritsky, E., Kessler, N., Baker, M.S., Zhu, S., Waterland, R.A. 2019. Early postnatal overnutrition accelerates aging-associated epigenetic drift in pancreatic islets. Environmental Epigenetics. 5(3):dvz015. https://doi.org/10.1093/eep/dvz015.
DOI: https://doi.org/10.1093/eep/dvz015

Interpretive Summary: It has been known for decades that overnutrition during infancy can lead to adverse long-term consequences for regulation of blood glucose and risk of type 2 diabetes. It is generally thought that such 'developmental programming' of diabetes risk is mediated, at least in part, by induced alterations in developmental epigenetics. Epigenetics is the study of the fundamental molecular mechanisms that restrict the gene expression potential of differentiated cell types – for example, what makes a liver cell different from a neuron, even though both cell types contain the same DNA. The epigenetic mechanism DNA methylation is the leading candidate, because of its long-term stability. We used a mouse model to investigate DNA methylation in developmental programming of type-2 diabetes. Mice were overnourished during the suckling period, and we performed genome-scale profiling of DNA methylation in pancreatic islets directly after weaning and in adulthood. (Pancreatic islets, also known as the 'endocrine pancreas', are responsible for secreting insulin and other hormones to regulated blood sugar levels.) At weaning, islets of overnourished mice exhibited a DNA methylation profile similar to that of islets of much older mice. This led us to postulate that postnatal overnutrition may lead to accelerated epigenetic aging.

Technical Abstract: Pancreatic islets of type 2 diabetes patients have altered DNA methylation, contributing to islet dysfunction and the onset of type 2 diabetes. The cause of these epigenetic alterations is largely unknown. We set out to test whether (i) islet DNA methylation would change with aging and (ii) early postnatal overnutrition would persistently alter DNA methylation. We performed genome-scale DNA methylation profiling in islets from postnatally over-nourished (suckled in a small litter) and control male mice at both postnatal day 21 and postnatal day 180. DNA methylation differences were validated using quantitative bisulfite pyrosequencing, and associations with expression were assessed by RT-PCR. We discovered that genomic regions that are hypermethylated in exocrine relative to endocrine pancreas tend to gain methylation in islets during aging (R2=0.33, P<0.0001). These methylation differences were inversely correlated with mRNA expression of genes relevant to B cell function [including Rab3b (Ras-related protein Rab-3B), Cacnb3 (voltage-dependent L-type calcium channel subunit 3), Atp2a3 (sarcoplasmic/endoplasmic reticulum calcium ATPase 3) and Ins2 (insulin 2)]. Relative to control, small litter islets showed DNA methylation differences directly after weaning and in adulthood, but few of these were present at both ages. Surprisingly, we found substantial overlap of methylated loci caused by aging and small litter feeding, suggesting that the age-associated gain of DNA methylation happened much earlier in small litter islets than control islets. Our results provide the novel insights that aging-associated DNA methylation increases reflect an epigenetic drift toward the exocrine pancreas epigenome, and that early postnatal overnutrition may accelerate this process.