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Genomic imprinting: parental influence on the genome

Key Points

  • Genomic imprinting leads to allele-specific expression depending on the parent of origin of the allele.

  • The most consistent difference between the alleles of an imprinted gene is in DNA methylation. But imprinted genes are also characterized by differences in chromatin conformation, histone modification, replication timing and recombination rate. The primary imprint causing these differences is unknown.

  • The life cycle of imprints involves erasure during early germ cell development, establishment later in germ cell development or after fertilization, and maintenance during embryonic development, and begins again with erasure in the germ cells of the embryo.

  • Genomic imprinting leads to imprinted gene expression. The mechanisms underlying this reading of the imprint can involve different aspects of gene expression: promoter methylation, the regulation of antisense transcripts, boundary elements, and silencers.

  • Imprinted genes are often found in clusters. These can be regulated by imprinting centres.

  • Dysregulation of imprinting has been found in many diseases: growth and behavioural defects (Beckwith–Wiedemann syndrome, Prader–Willi syndrome and Angelman syndrome) and cancer (Wilms tumour).

  • Imprinted genes are implicated in fetal–maternal physiology, and one theory for the evolution of imprinting (the conflict theory) is that it reflects the competing interests of the maternal and paternal genomes in the developing embryo.

Abstract

Genomic imprinting affects several dozen mammalian genes and results in the expression of those genes from only one of the two parental chromosomes. This is brought about by epigenetic instructions — imprints — that are laid down in the parental germ cells. Imprinting is a particularly important genetic mechanism in mammals, and is thought to influence the transfer of nutrients to the fetus and the newborn from the mother. Consistent with this view is the fact that imprinted genes tend to affect growth in the womb and behaviour after birth. Aberrant imprinting disturbs development and is the cause of various disease syndromes. The study of imprinting also provides new insights into epigenetic gene modification during development.

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Figure 1: Imprinting clusters in human and mouse genomes.
Figure 2: Characteristics of imprinted genes.
Figure 3: Life cycle of methylation imprints.
Figure 4: Methylation reprogramming in the germ line and embryo.
Figure 5: Reading mechanisms in imprinted genes.
Figure 6: Control of imprinting clusters by imprinting centres.

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Acknowledgements

We thank the many colleagues in our labs who are involved in imprinting work for discussions and comments on the manuscript, in particular W. Dean, M. Constancia, A. Murrell, R. Feil and G. Kelsey. We also thank three anonymous referees for excellent and constructive suggestions. Work in the authors' labs is supported by BBSRC, MRC, CRC, HFSP and DFG.

Author information

Affiliations

Authors

Related links

Related links

DATABASE LINKS

H19

Igf2

Cdkn1c

Dnmt1

Dnmt3a

Dnmt3b

Tsix

Xist

Igf2r

Kcnq1

Air

Kcnq1ot1

CTCF

Dlk

Gtl2

Prader–Willi syndrome

SNURF–SNRPN

Angelmann syndrome

Ins2

Beckwith–Wiedemann syndrome

Ins

Grb10

autism

bipolar affective disorder

schizophrenia

Tourette syndrome

Turner syndrome

UBE3A

Grf1

Ube3a

Peg1

Peg3

Wilms tumour

FURTHER INFORMATION

Harwell imprinting web site

Glossary

EUTHERIANS

Mammals that give birth to live offspring (viviparous) and possess an allantoic placenta.

CPG ISLAND

DNA region of >500 bp that has a high CpG density and is usually unmethylated. CpG islands are found upstream of many mammalian genes.

LINE-1 ELEMENT

A class of repetitive transposable element interspersed between and within genes throughout the genome. Most have degenerated and lost transposition activity.

SILENCER

DNA sequence at which repressor factors bind and mediate silencing of promoters through interaction with the basal transcriptional machinery or the enhancer.

BOUNDARY ELEMENT

DNA sequence that lies between two gene-controlling elements, such as a promoter and enhancer, preventing their communication or interaction. Boundary element function is usually mediated by the binding of specific factors.

DNASEI HYPERSENSITIVE SITE

Chromosomal region highly accessible to cleavage by deoxyribonuclease I (DNAseI). Such sites are associated with open chromatin conformations and transcriptional activity.

EPIGENOTYPE

Methylation and chromatin pattern of a gene or allele.

MONOTREMES

Non-eutherian, egg-laying mammals.

SPONGIOTROPHOBLAST

Junctional zone between the labyrinth and the maternal side of the placenta.

LABYRINTHINE TROPHOBLAST

Placental zone where fetal and maternal exchange takes place.

HYPERKINETIC, HYPOKINETIC

Exceeding (hyper) or reduced (hypo) movement of the body or extremeties.

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Reik, W., Walter, J. Genomic imprinting: parental influence on the genome. Nat Rev Genet 2, 21–32 (2001). https://doi.org/10.1038/35047554

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