DNA Methylation and Human Diseases: An Overview
Wolfgang A. Schulz and Olusola Y. Dokun
The importance of establishing and maintaining proper DNA methylation patterns is most dramatically highlighted by disturbances causing or contributing to human diseases. Mutations in components of the DNA methylation machinery underlie several inherited syndromes such as Immunodeficiency, Centromere instability, Facial anomalies (ICF) and Rett syndrome. Another group of congenital \"epigenetic\" diseases, exemplified by the Angelmann and Prader‑Willi syndromes is caused by defects in imprinting mechanisms. A third type of methylation disturbances occurs at expanding or contracting repeats in diseases like fragile X syndrome. Aberrant DNA methylation has also been associated with common acquired autoimmune, cardiovascular and neurological diseases, indicating important functions of DNA methylation in these systems. Moreover, gradually changing DNA methylation appears to represent a component of human aging that may predispose an individual to increased morbidity at older ages. The causes of altered methylation and its contribution to disease pathophysiology are best investigated, but still incompletely understood in human cancers. Two opposite, but often concurrent changes in DNA methylation are observed in many human malignancies. Hypermethylation at specific genes typically affects promoter CpG‑islands inactivating transcription. Hypermethylation events show a pronounced specificity for genes, cancer types and often even cancer progression stages and are therefore extremely useful for diagnostic purposes. In spite of locally increased DNA methylation in cancer cells, overall methylation levels are often decreased due to genome‑wide hypomethylation, particularly in repeat sequences and selected genes, such as cancer‑testis antigens. In addition, imprinting patterns are often disturbed. Together, DNA methylation changes in cancers contribute to altered patterns of gene expression, e.g., by silencing tumor suppressors, to genomic instability and altered cellular interactions, e.g., with the immune system. An intriguing hypothesis holds that early DNA methylation changes may crucially contribute to the generation of cancer stem cells. Recent research has highlighted the interaction of transcriptional repressors, chromatin modifiers and DNA methyltransferases in establishing hypermethylation, whereas the causes of hypomethylation are still poorly understood. Reversal of promoter hypermethylation is also explored as a promising approach for cancer therapy.