1.6.7 DNA Hypermethylation Definition

DNA Hypermethylation Definition is the description of an elevated 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 the acquisition of additional chemical marks that promote compaction of the local chromatin and reduce the accessibility of that DNA to the transcriptional machinery. DNA hypermethylation is most consequential when it occurs within the regulatory region located near the start of a gene, since methylation at this location is strongly associated with silencing of that gene's expression.

Conceptual Basis of DNA Hypermethylation

Hypermethylation as a Relative, Comparative Measure

Like its counterpart hypomethylation, DNA hypermethylation is defined relative to an expected baseline level of methylation at a given genomic region, meaning that a region is described as hypermethylated when its measured methylation level exceeds the level normally present at that region in corresponding normal tissue, rather than by reference to a fixed absolute quantity.

Concentration Within Regulatory Regions

DNA hypermethylation of greatest functional significance tends to occur within short stretches of DNA enriched in cytosine-guanine pairings that are located adjacent to the transcription start site of a gene, since these regions are normally maintained in an unmethylated state to allow ready access by the transcriptional machinery, making any abnormal gain of methylation at this location particularly disruptive to normal gene activity.

Mechanisms Producing DNA Hypermethylation

Aberrant Recruitment of Methylation-Establishing Enzymes

DNA hypermethylation can arise when the enzymes responsible for establishing new methylation marks are abnormally recruited to a regulatory region that would not normally be targeted for methylation, resulting in acquisition of methylation marks at a site that should otherwise remain accessible.

Failure of Mechanisms That Normally Protect Regulatory Regions

Certain cellular mechanisms normally act to keep the regulatory regions of genes protected from methylation, and disruption of these protective mechanisms can permit methylation to accumulate at a regulatory region that would otherwise have remained unmethylated throughout the cell's life.

Consequences of DNA Hypermethylation

Silencing of the Affected Gene

Hypermethylation of a gene's regulatory region reduces or eliminates the binding of proteins required to initiate transcription, and further attracts proteins that recognize methylated DNA and recruit additional chromatin-compacting factors, together producing a stable and durable silencing of the affected gene's expression.

Reinforcement Through Chromatin Compaction

The transcriptional silencing initially triggered by hypermethylation is reinforced by subsequent recruitment of chromatin-modifying complexes that further compact the local chromatin structure, producing a self-stabilizing silenced state that resists reactivation of the affected gene even under conditions that would normally support its expression.

Detection of DNA Hypermethylation

Comparative Methylation Profiling

DNA hypermethylation is identified by measuring the methylation level present at defined cytosine positions within a genomic sample and comparing this measurement to a corresponding reference profile obtained from normal tissue, with regions showing a substantial increase in methylation signal identified as hypermethylated.

Significance of DNA Hypermethylation Within Cancer Cell Biology

Silencing of Genes That Restrain Cell Growth

DNA hypermethylation is a recurrent mechanism by which cancer cells silence genes that would otherwise restrain cellular proliferation or promote programmed cell death, achieving a functional outcome equivalent to inactivation of these genes through direct genetic mutation, but through a chemical modification of an otherwise unaltered gene sequence.

Use as a Molecular Marker

Because hypermethylation at specific regulatory regions occurs recurrently and reproducibly across many tumors of a given type, the presence of hypermethylation at particular genes is used as a molecular marker for characterizing tumors and for identifying which regulatory genes have been functionally silenced within a given cancer cell population.