Role of DNA methylation in the dietary restriction mediated cellular memory

Archana Unnikrishnan,Jonathan D Wren,Karla P Garrett,Niran Hadad,Constantin Georgescu,Jordan Jackson,Arlan Richardson,Benjamin Wronowski,Willard M Freeman,Stephanie A Matyi

doi:10.1007/s11357-017-9976-8

Abstract

An important facet of dietary restriction (DR) that has been largely overlooked is that DR can have early effects that create a cellular memory, which persists even when DR is discontinued. The goal of this study was to determine if DNA methylation played a role in the cellular memory of DR by examining the effect of short-term DR on gene expression and DNA methylation and determining if the changes in expression and DNA methylation persist when DR is discontinued and mice returned to ad libitum (AL) feeding. We show that DR can induce substantial changes in gene expression within 1 month of its implementation in various tissues, and more interestingly, ~19–50% of these changes in gene expression persist across the tissues even when DR is discontinued. We then determined whether DR induced changes in DNA methylation in the promoter of three candidate genes identified from our gene expression analysis (Pomc, Hsph1, and Nts1) that correlated with the changes in the expression of these genes. Decreased methylation at three specific CG sites in the promoter of the Nts1 gene encompassing the distal consensus AP-1 site was correlated with increased Nts1 expression. Both the promoter hypomethylation and increased Nts1 expression persisted even after DR was discontinued and mice fed AL, supporting our hypothesis that DNA methylation could play a role in the memory effect of DR. The changes in DNA methylation in the Nts1 gene are likely to occur in intestinal stem cells and could play a role in preserving the intestinal stem cell pool in DR mice.

Highlights

DNA methylation is a molecular mechanism that has evolved to provide cellular memory to cells/organisms
It is becoming increasingly apparent that environmental/ nutritional factors can induce epigenetic changes (e.g., DNA methylation and histone modification), which can potentially result in long-term changes in gene expression and the function of cells and tissues in an organism
Recent studies have generated a great deal of interest in the possible role that DNA methylation might play in human aging, e.g., several groups showed that DNA methylation at specific CG sites was a quantitative chronological biomarker of human aging (Hannum et al 2013; Horvath 2013; Weidner et al 2014), and Melov’s group showed that changes in DNA methylation occurred at a number of genomic loci with age in human skeletal muscle that appeared to be associated with changes in gene expression (Zykovich et al 2014)

Summary

Introduction

DNA methylation is a molecular mechanism that has evolved to provide cellular memory to cells/organisms. Cytosines, especially those contained in CG dinucleotide motifs, are targeted for methylation (5mC) by DNA methyltransferases. McGhee and Ginder (1979) were the first to suggest that DNA methylation controlled gene expression, and Jones and Taylor (1980) showed that 5-azacytidine (an inhibitor of DNA methyltransferases) prevented the differentiation of cells by altering the expression of the genes involved in differentiation. It is accepted that DNA methylation can regulate the expression of specific genes and thereby potentially affect the physiological function of a cell/tissue over the lifetime of the organism

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