DNA methylation and human disease

Key Points

  • DNA methylation is an epigenetic modification of DNA that is important for the normal regulation of transcription, embryonic development, genomic imprinting, genome stability and chromatin structure.

  • DNA methylation is controlled by DNA methyltransferases, methyl-CpG binding proteins and other chromatin-remodelling factors.

  • Aberrations in the DNA methylation system have an important role in human disease.

  • DNA methylation patterns are globally disrupted in cancer, with genome-wide hypomethylation and gene-specific hypermethylation events occurring simultaneously in the same cell.

  • Loss of normal imprinting contributes to several inherited genetic diseases in humans. These diseases include Beckwith–Wiedemann, Prader–Willi, and Angelman syndromes, Albright hereditary osteodystrophy (AHO) and pseudohypoparathyroidism Ia (PHP-Ia) and PHP-Ib, and transient neonatal diabetes.

  • In vitro manipulation of embryos during assisted reproduction procedures might lead to imprinting defects in the offspring.

  • Abnormal expansion of a CGG repeat in the FMR1 gene, accompanied by its hypermethylation and silencing, leads to fragile X syndrome. By contrast, contraction and hypomethylation of a larger 3.3 kb repeat leads to facioscapulohumeral muscular dystrophy.

  • Mutations in the machinery that regulates DNA methylation patterns and chromatin structure also contribute to human disease. Mutations in DNMT3B and ATRX lead to immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome and Alpha-thalassemia/mental retardation syndrome, X-linked syndrome, respectively. Both disorders are characterized by localized disruptions in DNA methylation patterns.

  • The insulator/boundary proteins CCCTC-binding factor and BORIS, and the repression system known as RNAi, are probably involved in establishing and maintaining normal DNA methylation patterns.


DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, a growing number of human diseases have been found to be associated with aberrant DNA methylation. The study of these diseases has provided new and fundamental insights into the roles that DNA methylation and other epigenetic modifications have in development and normal cellular homeostasis.

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Figure 1: DNA methylation and cancer.
Figure 2: Regions involved in disease-associated genomic imprinting defects.
Figure 3: DNA methylation and diseases associated with repeat instability.
Figure 4: A model for the disruption of normal DNA methylation in cancer cells.


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I apologize to those whose work could not be cited owing to space limitations. Work in the author's lab is supported by the National Institutes of Health.

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Entrez gene

































Albright hereditary osteodystrophy

alpha-thalassemia/mental retardation syndrome, X-linked

Angelman syndrome

Beckwith–Wiedemann syndrome

facioscapulohumeral muscular dystrophy

fragile X syndrome

immunodeficiency, centromeric instability and facial anomalies syndrome

Prader–Willi syndrome

pseudohypoparathyroidism Ib

Rett syndrome

transient neonatal diabetes mellitus


The DNA methylation database

The DNA methylation society

Human Epigenome Project

The M. D. Anderson Cancer Center DNA Methylation in Cancer web site

The Genomic Imprinting Website

MRC Mammalian Genetics Unit Mouse Imprinting web site

CITE: Candidate Imprinted Transcript from gene Expression database

The DNMT3Bbase mutation registry for ICF syndrome



A genomic region of 1 kb that has a high G–C content, is rich in CpG dinucleotides and is usually hypomethylated.


Repression of one transcriptional unit by another such unit that is linked in cis.


(RLGS). A genome-wide method for analyzing the DNA methylation status of CpG islands. Radiolabelled fragments obtained by digestion with NotI (a methylation-sensitive restriction enzyme) are separated by two-dimensional gel electrophoresis, allowing differentiation between methylated and unmethylated regions.


A regulatory DNA element that usually binds several transcription factors and can activate transcription from a promoter at great distance and in an orientation-independent manner.


Inheritance of a chromosome or chromosome region from a single parent.


A condition in which two pieces of chromosomal material have switched places, but the correct number of chromosomes has been maintained.


Degradation pathway in which a protein that has been post-translationally modified with several ubiquitin polypeptides is targeted for destruction to the proteasome, a large cytosolic protein complex with several proteolytic activities.


A group of acidic, soluble, secretory proteins that are produced by neurons and neuroendocrine cells.


Short pieces of DNA that are synthesized on the lagging strand at the replication fork.


A region of chromatin that fails to compact normally during mitosis and that can be observed after culturing cells in media that is deficient in folic acid and thymidine.


The process whereby double-stranded RNAs are cleaved into 21–23 nucleotide duplexes termed small interfering RNAs, leading to inhibition of expression of genes that contain a complementary sequence.


A ribonuclease that processes dsRNAs to 21 nucleotide siRNAs (for RNAi) or excises microRNAs from their hairpin precursors.


Also known as a helper T cell. Initiates both antibody production by B cells and stimulates the activation of other immune cells, such as macrophages, after recognizing a portion of a protein antigen on the surface of an antigen presenting cell.


The process of conferring immunity to an individual by transferring cells or serum from another individual that has been immunized with a specific antigen.


macrophages (immune cells that engulf foreign particles) that are transferred between genetically identical mice.


Immortalized B cell line created by infecting primary B cells with Epstein-Barr virus.


ATP-dependent chromatin remodelling enzymes that contain a region homologous to an extended family of proteins that include known RNA and DNA helicases.


Dot-like structures in the nucleus of most mammalian cells. These were originally defined by the localization of the PML protein, which is involved in transcriptional regulation.

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Robertson, K. DNA methylation and human disease. Nat Rev Genet 6, 597–610 (2005). https://doi.org/10.1038/nrg1655

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