Elsevier

Nutrition

Volume 20, Issue 1, January 2004, Pages 63-68
Nutrition

Epigenetics and epistasis
Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases

https://doi.org/10.1016/j.nut.2003.09.011Get rights and content

Introduction

Several recent reviews surveying the promising field of nutrigenomics1, 2 have not discussed the important role that epigenetic mechanisms play at the nexus between nutrition and the genome. This is a glaring omission. Certainly, “nutrient–gene interactions” in humans enable various nutrients to transiently influence the expression of specific subsets of genes. In addition to these phenomena, however, it is becoming increasingly evident that by interacting with epigenetic mechanisms, which regulate chromatin conformation across entire genomic regions, transient nutritional stimuli at critical ontogenic stages can wield lasting influences on the expression of various genes.3 Moreover, such epigenetic changes, if they occur in the gametes, may be heritable. This review focuses on early nutritional influences on cytosine methylation. It proposes that certain genomic regions, including genomically imprinted domains and specific transposon insertion sites, are especially labile to such influences. Considering the critical roles that genomically imprinted genes play in mammalian growth and development4 and the huge proportion of our genome that is comprised of transposons,5 early nutritional influences on these genomic components could have a substantial impact on human health. Genomic and epigenetic similarities between these distinct classes of elements are elaborated, and key areas of future research are discussed.

Section snippets

Early nutrition and adult disease

Extensive human epidemiologic data have indicated that prenatal and early postnatal nutrition influence adult susceptibility to diet-related chronic diseases including cardiovascular disease, type 2 diabetes, obesity, and cancer.6, 7, 8, 9, 10 These epidemiologic data are bolstered by numerous studies in animal models10, 11 clearly showing that subtle nutritional influences during development can influence adult metabolism. Understanding the specific biologic mechanisms underlying such

Early nutrition and DNA methylation

Epigenetic information is conveyed in mammals via a synergistic interaction between mitotically heritable patterns of DNA methylation and chromatin structure.18 This review focuses on the epigenetics of cytosine methylation, which occurs on both strands of palindromic CpG dinucleotides in mammals. CpG methylation (the “p” in “CpG” denotes the intervening phosphate group in the dinucleotide), which is critical for mammalian development,19 affects transcription directly by influencing the binding

Epigenetic lability of genomically imprinted genes

We carry two copies of all autosomal genes, and the vast majority of these are expressed equally from the paternally inherited and maternally inherited alleles. Some mammalian genes, however, are expressed preferentially from the paternal or maternal allele and are said to be genomically imprinted. The term imprinted conveys that these genes must somehow be differentially “marked” in sperm and ova so the developing embryo can distinguish between them. All current data indicate that this marking

Epigenetic lability of transposons

Transposons are parasitic, repetitive mobile elements that are dispersed throughout the genome and can be classified as DNA transposons (which transpose by a direct DNA “cut-and-paste” mechanism) or retrotransposons (which transpose via an RNA intermediate).37 Retrotransposons are by far the predominant class of transposons in the mammalian genome. They are grouped into two broad classes: long-terminal repeat (LTR)–containing retrotransposons, such as human endogenous retroviruses, and non-LTR

Genomic and epigenetic similarities of imprinted genes and transposons

Genomically imprinted genes and specific transposon insertion sites at first may seem to not have much in common. A close inspection, however, reveals that these apparently disparate genomic elements share several genomic and epigenetic characteristics that might help us understand their apparent enhanced epigenetic susceptibility to the influence of early nutrition.

The most obvious such shared characteristic is that imprinted genes and transposons are transcriptionally regulated by CpG

Future directions: nutritional epigenomics

New technologies now make it possible to test the hypothesis that specific genomic regions have an enhanced epigenetic lability to nutritional (and other environmental) influences during development. Rather than using genomic approaches to identify genes whose expression is persistently altered by early nutrition, epigenomic approaches now promise the potential to measure gene-specific changes in DNA methylation of many genes simultaneously. Genome-wide methylation profiling offers important

First page preview

First page preview
Click to open first page preview

References (67)

  • R.A. Waterland et al.

    Early postnatal nutrition determines adult pancreatic glucose- responsive insulin secretion and islet gene expression in rats

    J Nutr

    (2002)
  • J.A. Yoder et al.

    Cytosine methylation and the ecology of intragenomic parasites

    Trends Genet

    (1997)
  • P. Nigumann et al.

    Many human genes are transcribed from the antisense promoter of L1 retrotransposon

    Genomics

    (2002)
  • P. Medstrand et al.

    Long terminal repeats are used as alternative promoters for the endothelin B receptor and apolipoprotein C-I genes in humans

    J Biol Chem

    (2001)
  • P.A. Yates et al.

    Tandem B1 elements located in a mouse methylation center provide a target for de novo DNA methylation

    J Biol Chem

    (1999)
  • V.K. Rakyan et al.

    Metastable epialleles in mammals

    Trends Genet

    (2002)
  • K.L. Arney

    H19 and Igf2-enhancing the confusion?

    Trends Genet

    (2003)
  • A.F. Smit

    Interspersed repeats and other mementos of transposable elements in mammalian genomes

    Curr Opin Genet Dev

    (1999)
  • T. Sakatani et al.

    Epigenetic heterogeneity at imprinted loci in normal populations

    Biochem Biophys Res Commun

    (2001)
  • J.G. Falls et al.

    Genomic imprintingimplications for human disease

    Am J Pathol

    (1999)
  • M. Weber et al.

    Extensive tissue-specific variation of allelic methylation in the Igf2 gene during mouse fetal developmentrelation to expression and imprinting

    Mech Dev

    (2001)
  • S. Maier et al.

    Diabetesa candidate disease for efficient DNA methylation profiling

    J Nutr

    (2002)
  • R. Tompa et al.

    Genome-wide profiling of DNA methylation reveals transposon targets of CHROMOMETHYLASE3

    Curr Biol

    (2002)
  • M. Muller et al.

    Nutrigenomicsgoals and strategies

    Nat Rev Genet

    (2003)
  • R. Jaenisch et al.

    Epigenetic regulation of gene expressionhow the genome integrates intrinsic and environmental signals

    Nat Genet

    (2003)
  • W. Reik et al.

    Genomic imprintingparental influence on the genome

    Nat Rev Genet

    (2001)
  • S. Frankel et al.

    Childhood energy intake and adult mortality from cancerthe Boyd Orr Cohort Study

    BMJ

    (1998)
  • D.A. Leon

    Fetal growth and adult disease

    Eur J Clin Nutr

    (1998)
  • A. Lucas

    Programming by early nutrition in man

    Ciba Found Symp

    (1991)
  • K.M. Rasmussen

    The “fetal origins” hypothesischallenges and opportunities for maternal and child nutrition

    Annu Rev Nutr

    (2001)
  • D.J. Barker

    Programming the baby

  • Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation....
  • A. Bird

    DNA methylation patterns and epigenetic memory

    Genes Dev

    (2002)
  • Cited by (0)

    This work was supported by a Dannon Institute fellowship (R.A.W.), American Cancer Society grant PF-03-171-01-CNE, and NIH grants CA25951 and ES08823.

    View full text