Our bodies are made of cells, and within each cell lies DNA, the instruction manual for life. This DNA is composed of building blocks called nucleotides, arranged in specific sequences. A particular sequence of interest is the CpG dinucleotide, which refers to a cytosine (C) nucleotide immediately followed by a guanine (G) nucleotide on the same DNA strand, linked by a phosphate bond. This specific arrangement is distinct from a C-G base pair that occurs across the two strands of the DNA double helix.
Understanding CpG Dinucleotides
CpG dinucleotides are not evenly distributed throughout the human genome. In fact, they are relatively rare compared to other dinucleotide sequences, occurring at about 20% of the predicted frequency in the genome. This underrepresentation is thought to be due to an increased vulnerability of methylated cytosines within CpG sites to undergo a specific type of mutation, leading to their conversion into thymines over evolutionary time.
Despite their general scarcity, CpG dinucleotides are found in higher concentrations in specific regions known as “CpG islands.” These islands are defined as DNA segments at least 200 base pairs long, with a high GC content (over 50%) and a higher-than-expected ratio of CpG dinucleotides. CpG islands are often located near the start of genes, particularly in the promoter regions which control gene activity. Approximately 60% of human gene promoters are associated with these CpG islands.
The Dynamic Process of Methylation
DNA methylation is a chemical modification where a methyl group (-CH3) is added to the cytosine base at CpG sites. This modification does not alter the underlying DNA sequence but can profoundly influence how genes are expressed. The process of DNA methylation is carried out by a family of enzymes called DNA methyltransferases (DNMTs).
These enzymes identify CpG sites and transfer a methyl group to the cytosine, converting it into 5-methylcytosine. This modification is not permanent; DNA demethylation can also occur through both passive and active mechanisms. Passive demethylation happens during cell division when DNMTs are absent or non-functional, leading to the loss of 5-methylcytosine. Active demethylation involves a series of enzymatic steps.
CpG Methylation and Gene Regulation
Methylation at CpG sites, particularly within gene promoter regions, influences gene activity. Methylation at these locations leads to gene silencing, effectively turning genes off. This silencing can occur in two main ways: directly, by physically blocking transcription factors from binding to the DNA, or indirectly, by recruiting specific proteins.
These proteins, known as methyl-CpG-binding domain proteins (MBDs), bind to the methylated DNA. Once bound, MBDs recruit other protein complexes. These complexes remove acetyl groups from histone proteins, around which DNA is wound, leading to a more compact and inaccessible chromatin structure. This compacted chromatin makes it difficult for the cellular machinery responsible for gene transcription to access the DNA, thus repressing gene expression. This mechanism is observed in normal cellular processes like cell differentiation and genomic imprinting, where specific DNA methylation patterns silence genes.
CpG Dinucleotides in Health and Disease
Maintaining proper CpG methylation patterns is important for overall health. However, abnormal methylation patterns (hypermethylation or hypomethylation) are associated with various diseases. In cancer, for instance, aberrant methylation is a common feature.
Hypermethylation of CpG islands in the promoter regions of tumor suppressor genes can silence these genes, which normally help regulate cell growth and prevent cancer development. Conversely, hypomethylation can occur in other genomic regions, leading to genomic instability and the activation of oncogenes—genes that promote cell growth and differentiation. Beyond cancer, altered CpG methylation patterns have been linked to neurological disorders like Alzheimer’s and Parkinson’s diseases, and the aging process itself. Age-related changes in methylation can contribute to the increased risk of certain diseases as individuals get older.