1.6.6 DNA Hypomethylation Definition

DNA Hypomethylation Definition is the description of a reduced level of methylation present at cytosine bases within a genomic region, relative to the level of methylation normally present at that same region in a corresponding healthy cell, resulting in a loss of the chemical marks that would ordinarily contribute to compaction and transcriptional silencing of that DNA. DNA hypomethylation can occur at a broad, genome-wide scale, affecting large stretches of DNA that lie outside of gene regulatory regions, or it can occur locally at the regulatory region of a specific gene, and the functional consequences of hypomethylation differ substantially depending on which of these patterns is present.

Conceptual Basis of DNA Hypomethylation

Hypomethylation as a Relative, Comparative Measure

DNA hypomethylation is defined by comparison to an expected baseline level of methylation, meaning that a region is described as hypomethylated when its measured methylation level falls below the level normally observed at that same region in the corresponding normal, non-cancerous tissue, rather than by reference to any fixed absolute threshold.

Distribution Across Distinct Genomic Contexts

Hypomethylation can occur within two broadly distinct genomic contexts, each carrying different functional implications. Loss of methylation across the large repetitive and structural stretches of DNA that make up much of the genome outside of individual genes has different consequences than loss of methylation confined specifically to the regulatory region located near the start of an individual gene.

Mechanisms Producing DNA Hypomethylation

Passive Loss of Methylation During Cell Division

Hypomethylation can arise passively when the enzymatic machinery responsible for reproducing an existing methylation pattern on newly synthesized DNA fails to act efficiently during repeated rounds of cell division, resulting in a gradual dilution of methylation marks across successive cell generations.

Active Removal of Methylation Marks

Hypomethylation can also arise through active enzymatic removal of methylation marks, in which dedicated enzymes convert methylated cytosine bases into unmodified or intermediate forms that are subsequently recognized and completed by cellular repair processes, restoring the site to an unmethylated state.

Consequences of DNA Hypomethylation

Genome-Wide Hypomethylation and Structural Instability

Loss of methylation across the broad repetitive stretches of the genome is associated with increased mobility of repetitive genetic elements and with a reduced ability of the cell to maintain stable chromosomal structure, contributing to broader genomic instability and to an increased frequency of chromosomal rearrangement.

Localized Hypomethylation and Inappropriate Gene Activation

Loss of methylation confined to the regulatory region of a specific gene removes a chemical mark that would otherwise contribute to silencing of that gene, and can therefore result in inappropriate activation or overexpression of that gene, particularly when the gene in question would not normally be active in that cellular context.

Detection of DNA Hypomethylation

Comparative Methylation Profiling

DNA hypomethylation is identified by directly measuring the methylation level present at defined cytosine positions across a genomic sample and comparing the resulting profile to a reference profile obtained from corresponding normal tissue, with regions showing a substantial reduction in methylation signal identified as hypomethylated.

Significance of DNA Hypomethylation Within Cancer Cell Biology

A Recurrent and Widespread Feature of Cancer Genomes

DNA hypomethylation, particularly across the broad repetitive stretches of the genome, is one of the most consistently observed epigenetic abnormalities across many different cancer types, frequently appearing early in the course of tumor development and contributing to the overall genomic instability characteristic of cancer cells.

Cooperation With Localized Hypermethylation

Cancer genomes commonly display genome-wide hypomethylation occurring simultaneously with localized hypermethylation at the regulatory regions of specific genes, illustrating that these two seemingly opposite methylation abnormalities are not mutually exclusive but instead frequently coexist within the same cancer cell genome, each contributing distinct consequences to the abnormal cellular state.