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DNA methylation in health and disease

Nature Reviews Genetics volume 1, pages 11–19 (2000)Cite this article

Abstract

DNA methylation has recently moved to centre stage in the aetiology of human neurodevelopmental syndromes such as the fragile X, ICF and Rett syndromes. These diseases result from the misregulation of genes that occurs with the loss of appropriate epigenetic controls during neuronal development. Recent advances have connected DNA methylation to chromatin-remodelling enzymes, and understanding this link will be central to the design of new therapeutic tools.

Key Points

Summary:

  • DNA methylation is the most common covalent modification of the human genome.

  • DNA methylation is important in imprinting, X-inactivation, cancer and for the developmental control of gene expression.

  • DNA methylation is directly connected to transcriptional repression through chromatin-remodelling complexes

  • Mutations in DNMT3B lead to ICF syndrome, a rare, recessive autosomal disorder.

  • Mutations in the methyl-CpG-binding protein MeCP2 lead to Rett syndrome.

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Figure 1: DNA methylation, CpG islands and genome defence.
Figure 2: Schematic structure of the three catalytically active DNA methyltransferases in mammals showing the N-terminal regulatory and C-terminal catalytic domains, and other regions with known or proposed functions.
Figure 3: Summary of mutations identified in the MECP2 protein in people with Rett syndrome62,88.
Figure 4: The mechanism whereby DNA methylation and histone deacetylation cooperate to repress transcription.
Figure 5: Summary of mutations in DNA methyltransferase 3B (DNMT3B) identified in ICF syndrome patients3,83,84.
Figure 6: Schematic of the fragile X mental retardation 1 (FMR1) gene showing the location of the CGG repeat within the 5′-untranslated region of exon 1.

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Authors and Affiliations

  1. Epigenetic Gene Regulation and Cancer Section, NCI, NIH, Building 41, 41 Library Drive, Bethesda, 20892-5431, Maryland, USA

    Keith D. Robertson

  2. Sangamo Biosciences, Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, 94804, California , USA

    Alan P. Wolffe

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  1. Keith D. Robertson
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Correspondence to Alan P. Wolffe.

Supplementary information

Related links

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DATABASE LINKS

ICF syndrome

Rett syndrome

Fragile X syndrome

TP53

DNMT1

DNMT3A

DNMT3B

DNMT1-like protein in Drosophila

DNMT2 homologue in Drosophila

Dnmt3a

Dnmt3b

E2F1

HDAC1

HDAC2

DMAP1

TSG101

MECP2

MBD1

MBD2

MBD3

RbAp46/48

MECP1

MBD2/3 in Drosophila

ATRX gene

ATRX syndrome

FMR1 gene

FURTHER INFORMATION

Histone sequence database

DNA methylation society

Glossary

HETEROCHROMATIN

The densely staining regions of the nucleus that generally contain condensed, transcriptionally inactive regions of the genome.

EUCHROMATIN

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

BLASTOCYST

An early stage of embryonic development at which cells begin to commit to certain developmental lineages.

IMPRINTING

A genetic mechanism by which genes are selectively expressed from the maternal or paternal chromosomes.

CPG ISLAND

A genomic region of about one kilobase that contains close to the theoretical, expected frequency of the CpG dinucleotide.

NUCLEOSOME

The basic structural subunit of chromatin, which consists of roughly 200 base pairs of DNA and an octamer of histone proteins.

DEAMINATION

(of cytosine) The reaction of a water molecule with the amino-group on position 4 of the pyrimidine ring of cytosine, which results in the conversion of cytosine to uracil.

RETROTRANSPOSON

A mobile genetic element; its DNA is transcribed into RNA, which is reverse-transcribed into DNA and then is inserted into a new location in the genome.

L1 OR LINE ELEMENT

Long interspersed sequences generated by RNA polymerase II transcripts.

ALU OR SINE ELEMENT

Short interspersed sequences generated by RNA polymerase III transcripts. An Alu is one of several different SINEs and it requires factors encoded by other retrotransposons (reverse transcriptase) to proliferate.

INTRACISTERNAL A PARTICLE (IAP)

A mouse L1-like element.

V(D)J RECOMBINATION

A specialized form of recombination that assembles the genes that encode lymphocyte antigen receptors from variable (V), diversity (D) and joining (J) gene segments. DNA double-strand breaks are introduced between the V, D and J segments and DNA repair proteins then join the segments together.

5-AZA-2′-DEOXYCYTIDINE (5-AZA-CDR)

A potent and specific inhibitor of DNA methylation.

HETEROLOGOUS GAL4 DNA-BINDING DOMAIN

A protein that is fused to the DNA-binding domain of the yeast GAL4 protein to determine its effect on transcription.

TFIIB

Transcription factor IIB, a critical component of the basal transcription machinery.

TRICHOSTATIN A (TSA)

A specific inhibitor of histone deacetylase.

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Robertson, K., Wolffe, A. DNA methylation in health and disease. Nat Rev Genet 1, 11–19 (2000). https://doi.org/10.1038/35049533

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