The question of whether methylation increases gene activity, known as transcription, involves epigenetics—a system that controls how genes are used without changing the underlying DNA sequence. Epigenetics governs which genes are turned “on” or “off” in a cell, allowing different cell types—like a nerve cell and a skin cell—to function distinctly despite sharing the exact same genetic code. DNA methylation is one such epigenetic modification, involving the addition of a small chemical tag called a methyl group to the DNA strand.
Foundational Concepts of Gene Regulation
Gene regulation is the process by which a cell controls the timing, location, and amount of protein production from its genes. This control is necessary for proper development and for cells to respond to their environment. Transcription is where the DNA sequence of a gene is copied into a messenger RNA molecule by an enzyme called RNA polymerase. This RNA molecule then carries the instructions for building a protein.
DNA methylation involves the specific addition of a methyl group to a cytosine base, forming 5-methylcytosine. This modification occurs predominantly at CpG dinucleotides (cytosine followed by guanine). Clusters of these CpG sites, called CpG islands, are often located in the promoter regions of genes, which are the starting points for transcription. Methylation is a primary tool for achieving selectivity in gene regulation.
The Primary Outcome: Transcriptional Repression
The direct answer is that DNA methylation typically acts as a gene silencer, leading to a decrease in transcription. When methyl groups are placed on a gene’s promoter region, the gene is turned off. This inverse relationship—more methylation equals less transcription—is a fundamental principle of gene control in mammals.
Transcriptional repression serves several biological purposes across the lifespan of an organism. Methylation is used to silence mobile DNA elements (transposons), which protects the stability of the entire genome. It is also responsible for processes like X-chromosome inactivation and genomic imprinting, where only the gene copy inherited from one parent is expressed. Methylation is a mechanism for tissue-specific gene silencing.
Molecular Mechanisms of Gene Silencing
DNA methylation causes repression through two primary molecular mechanisms that make the DNA inaccessible to the transcriptional machinery. The first is steric hindrance, where the added methyl group physically blocks the access of proteins needed for transcription. Transcription factors, which must bind to the DNA promoter to initiate transcription, are prevented from attaching by the methyl group. Methylation effectively covers the recognition sequence, making the DNA unreadable.
The second mechanism involves the recruitment of specialized proteins that modify the surrounding DNA structure. Methylated DNA attracts Methyl-CpG-Binding Domain proteins (MBDs). MBDs act as a docking site for protein complexes that contain enzymes like histone deacetylases (HDACs). These HDACs remove acetyl groups from the histone proteins, leading to condensed chromatin. This tightly wound state physically locks the DNA, making it inaccessible to the transcription machinery.
The Activating Role of Histone Modifications
Confusion over whether methylation increases transcription often stems from the distinction between DNA methylation and histone methylation, which is a different type of epigenetic mark. Histones are the spool-like proteins that DNA wraps around to form chromatin. Histone methylation can have opposite effects on transcription depending on the specific location and amino acid residue that receives the methyl group.
Some histone methylation marks are associated with transcriptional activation, meaning they turn genes on. For example, the trimethylation of the fourth lysine residue on histone H3 (H3K4me3) is a recognized signal for actively transcribed gene promoters. These marks help to create an open, relaxed chromatin structure, making the DNA available to the transcription machinery.
Conversely, other histone methylation marks are associated with repression, similar to the action of DNA methylation. The trimethylation of the ninth and twenty-seventh lysine residues on histone H3 (H3K9me3 and H3K27me3) are signals for gene silencing and the formation of condensed chromatin. The complexity of histone modifications demonstrates that the term “methylation” does not have a single effect on gene activity across all biological molecules.