Review Article | Published:

Chromatin modification and epigenetic reprogramming in mammalian development

Nature Reviews Genetics volume 3, pages 662673 (2002) | Download Citation

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Abstract

The developmental programme of embryogenesis is controlled by both genetic and epigenetic mechanisms. An emerging theme from recent studies is that the regulation of higher-order chromatin structures by DNA methylation and histone modification is crucial for genome reprogramming during early embryogenesis and gametogenesis, and for tissue-specific gene expression and global gene silencing. Disruptions to chromatin modification can lead to the dysregulation of developmental processes, such as X-chromosome inactivation and genomic imprinting, and to various diseases. Understanding the process of epigenetic reprogramming in development is important for studies of cloning and the clinical application of stem-cell therapy.

Key points

  • The principal epigenetic mechanisms by which tissue-specific gene-expression patterns and global gene silencing are established and maintained are chromatin modification — including processes such as DNA methylation, histone modification (acetylation, phosphorylation, methylation and ubiquitylation) — and chromatin remodelling.

  • New data show how DNA methylation and histone modification integrate with each other in the epigenetic regulation of genomic imprinting, X inactivation and genome reprogramming.

  • DNA methylation is the heritable epigenetic mark for genomic imprinting, which is established in the developing oocyte and is essential for maintaining the mono-allelic expression of imprinted genes. DNA methyltransferase Dnmt3a and an associated protein Dnmt3l, and the histone methyltransferases Suv39h1 and Suv39h2, are required for spermatogenesis.

  • DNA methylation undergoes dynamic changes during early embryonic development, and genome-wide demethylation (after fertilization) and remethylation (after the implantation of a blastocyst) have an essential role in genome reprogramming.

  • X inactivation is regulated by several factors, including non-coding RNAs (Xist and Tsix), DNA methylation, histone acetylation and deacetylation, histone methylation and Polycomb-group proteins.

  • Reprogramming of somatic cell nuclei in enucleated oocytes by nuclear transfer resets the epigenetic programme for embryonic development.

  • Studies of the epigenetic regulation of chromatin and gene expression in development will help to elucidate the underlying causes of certain human diseases. A greater understanding of these processes will also aid research into the clinical application of pluripotent stem cells or progenitor cells in cell-replacement therapy and into new drugs that target epigenetic regulators for use in treating cancer and certain developmental disorders.

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Acknowledgements

I am indebted to members of my lab for stimulating discussion and comments on the manuscript and to many colleagues in the field for discussion during the preparation of this review. Research in my laboratory is supported by the National Institutes of Health.

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  1. Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA. en@cvrc.mgh.harvard.edu

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Glossary

HISTONES

Small, highly conserved basic proteins, found in the chromatin of all eukaryotic cells, which associate with DNA to form a nucleosome.

CORE HISTONES

These are histones H2A, H2B, H3 and H4. A nucleosome contains two copies of each of the core histones wrapped by 146-bp DNA.

EUCHROMATIN

The lightly staining regions of the nucleus that generally contain decondensed, transcriptionally active regions of the genome.

HETEROCHROMATIN

A cytologically defined genomic component that contains repetitive DNA (highly repetitive satellite DNA, transposable elements and ribosomal DNA gene clusters) and some protein-coding genes.

EPIGENETIC

Any heritable influence (in the progeny of cells or of individuals) on chromosome or gene function that is not accompanied by a change in DNA sequence. Examples of epigenetic events include mammalian X-chromosome inactivation, imprinting, centromere inactivation and position effect variegation.

CHROMATIN MODIFICATION

Includes processes such as DNA methylation and histone modification (acetylation, phosphorylation, methylation and ubiquitylation).

CHROMATIN REMODELLING

Transient changes in chromatin accessibility.

NUCLEOSOME

The fundamental unit into which DNA and histones are packaged in eukaryotic cells. It is the basic structural subunit of chromatin and consists of 200 bp of DNA and an octamer of histone proteins, comprising two of each core histone.

SET DOMAIN

(Suvar3–9, Enhancer-of-zeste, Trithorax) domain. An evolutionarily conserved sequence motif that was initially identified in the Drosophila position effect variegation suppressor Su(var)3–9, the Polycomb-group protein Enhancer-of-zeste, and the Trithorax-group protein Trithorax. It is present in many histone methyltransferases and is required for enzyme activity.

HETEROCHROMATIN PROTEIN 1

(HP1). A protein that binds to highly repetitive, heterochromatic satellite DNA at centromeres and telomeres.

CHROMODOMAIN

A highly conserved sequence motif that has been identified in various animal and plant species. Chromodomain proteins are often structural components of large macromolecular chromatin complexes or are involved in remodelling chromatin structure.

GASTRULATION

A morphogenetic process that leads to the formation of the mesoderm layer between the endoderm and ectoderm layers and to the formation of embryonic body patterns.

DIFFERENTIALLY METHYLATED REGION

(DMR). DNA segments in imprinted genes that show different methylation patterns between paternal and maternal alleles. Some DMRs acquire DNA methylation in the germ cells, whereas others acquire DNA methylation during embryogenesis.

PRONUCLEUS

The sperm nucleus or the egg nucleus in a fertilized egg before a single nucleus forms.

BLASTOCYST

A pre-implantation embryo that contains a fluid-filled cavity called a blastocoel.

INNER CELL MASS

(ICM). A small clump of apparently undifferentiated cells in the blastocyst, which gives rise to the entire fetus and some of its extra-embryonic membranes.

TROPHOBLAST

The post-implantation derivatives of the trophectoderm, which make up most of the fetal part of the placenta.

PRIMITIVE ENDODERM

An early differentiated cell type that lines the inner surface of the blastocyst cavity. It gives rise to the endoderm component of the extra-embryonic membranes.

YOLK SAC

An extra-embryonic membrane that consists of an outer endoderm layer and an inner mesoderm layer, which surrounds the developing embryo.

TROPHECTODERM

The outer epithelial layer of the blastocyst.

PLURIPOTENCY

The ability of a cell to contribute to several tissues in a developing organism. If a cell is able to contribute to all tissues, it is said to be totipotent.

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