DNA methylation is a chemical modification to DNA influencing how genetic information is utilized. It involves adding a methyl group, a small chemical tag, typically to the cytosine base within a CpG dinucleotide sequence. Transcription is the initial step in gene expression, copying DNA’s genetic blueprint into an RNA molecule. This process allows cells to access gene instructions. DNA methylation acts as an “off switch,” repressing or silencing nearby genes.
Understanding Gene Expression
A gene is a segment of DNA containing instructions for making an RNA molecule, often leading to a protein. For gene expression, RNA polymerase must bind to the promoter region, a specific DNA sequence upstream of the gene. Promoters serve as binding sites for RNA polymerase and transcription factors. These transcription factors recognize specific sequences, such as the TATA box, within the promoter, helping position RNA polymerase.
Once RNA polymerase and transcription factors are in place, they form a transcription initiation complex. RNA polymerase unwinds a section of the DNA double helix, creating a “transcription bubble.” One separated DNA strand, the template strand, is used by RNA polymerase to synthesize a complementary RNA molecule. This RNA molecule carries the genetic message for cellular use.
How DNA Methylation Suppresses Transcription
DNA methylation reduces gene transcription through two mechanisms. The first involves direct interference: methyl groups physically obstruct transcription factor binding to DNA. Many transcription factors require direct contact with specific cytosine bases in the DNA’s major groove to bind to target sites, especially in promoter regions. When methylated, the bulky methyl group acts as a physical barrier, preventing protein attachment and transcription initiation.
The second mechanism involves indirect chromatin remodeling. Methylated DNA, especially in CpG-rich areas, recruits Methyl-CpG-binding domain (MBD) proteins (e.g., MeCP2, MBD1, MBD2, MBD3). These MBD proteins do not directly block transcription but serve as adapters for other enzyme complexes. They notably recruit histone deacetylases (HDACs).
Histones are proteins around which DNA is wound, forming nucleosomes that make up chromatin. Histone deacetylases remove acetyl groups from histone tails, a modification that normally keeps chromatin open and accessible for transcription. This removal causes DNA to wrap more tightly around histones, leading to a more compact, condensed chromatin structure, often referred to as heterochromatin. This tightly packed state restricts RNA polymerase and transcription machinery access to DNA, effectively silencing the gene.
Why DNA Methylation Matters
The ability of DNA methylation to suppress gene transcription has widespread biological implications. It is a fundamental mechanism in gene silencing, which is observable during organismal development and cellular differentiation. For instance, de novo methylation patterns are established during early embryogenesis, guiding cells to develop into specific tissues by activating some genes and silencing others. This ensures that only genes relevant to a particular cell type are expressed, contributing to the diversity of cell functions within an organism.
DNA methylation also plays a significant role in dosage compensation, such as X-chromosome inactivation in female mammals. Females have two X chromosomes, while males have one; to balance the gene dosage, one of the female X chromosomes is largely silenced through extensive DNA methylation and compaction into a transcriptionally inactive structure called a Barr body. Furthermore, it is involved in genomic imprinting, a process where only one parental copy of a gene is expressed, while the other is silenced via methylation.
Beyond gene regulation, DNA methylation is crucial for maintaining genome stability. It helps to silence repetitive DNA elements, such as LINEs, Alus, and satellites, as well as remnants of viral DNA that are integrated into the genome. Most of these repetitive elements are heavily methylated, preventing their activation and potential movement within the genome, which could otherwise lead to harmful mutations or genomic instability.
Alterations in DNA methylation patterns are also frequently linked to various diseases, particularly cancer. In many cancers, there is a widespread decrease in overall DNA methylation (global hypomethylation), which can lead to genomic instability and the inappropriate activation of oncogenes. Concurrently, specific regions, especially CpG islands in the promoter regions of tumor suppressor genes, often become abnormally hypermethylated. This hypermethylation silences these protective genes, removing crucial brakes on cell growth and division, thus contributing to tumor development.