The role of age-related DNA methylation in the development of age-related disease

Abstract

Alterations in DNA methylation can have dramatic effects on gene transcription, and in particular, hypermethylation of promoter associated CpG islands is known to lead to gene inactivation. Altered patterns of DNA methylation play a key role in the development of cancer and may also play important roles in many other diseases. However, the mechanisms which lead to these changes in DNA methylation are unknown. DNA methylation patterns have also been found to change during normal ageing and these changes have similarities to those that occur during the development of cancer. This suggests that for some age-related diseases, most notably cancer, altered patterns of methylation may be an early initiating event and that disease may develop in cells which already possess changes in their DNA methylation landscape. Therefore, this study was designed to examine how methylation levels at a group of genes alters over the life-course and how these relate to methylation changes observed in major age-related diseases (cancer, specifically acute lymphoblastic leukaemia (ALL) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) patients, and atherosclerosis). DNA was collected from healthy volunteers from different ages and from ALL, HNPCC and atherosclerosis patients. Methylation was quantified using pyrosequencing. The study produced a number of findings: 1) Genes exhibiting variable methylation in PBL samples from healthy volunteers are also highly methylated in leukaemia, suggesting a common underlying mechanism. 2) Increased methylation levels were observed in lymphoid compared to myeloid cells, in healthy individuals, mirroring the patterns seen in leukaemia. 3) A subset of genes exhibiting variable methylation in PBL samples from healthy volunteers and that are highly methylated in leukaemia are aberrantly methylated in HNPCC patients and atherosclerosis patients, suggesting shared risk factors. 4) While methylation levels increase during ageing, a substantial proportion of methylation is already present at birth and may thus alter disease susceptibility throughout life. 5) Blood samples from ALL patients in remission exhibit increased methylation levels (versus controls), not directly related to their leukaemic clone, and the extent of methylation correlates with overall survival. The studies to date are compatible with a hypothesis in which altered methylation of disease-related genes pre-exists in a subset of haematopoietic cells and that these cells may be at a significantly increased risk of progression to age-related diseases. Furthermore, monitoring DNA methylation may be a valuable tool for early diagnosis of these diseases, as well as for monitoring disease progression in patients.