Table of Contents
DNA Methylation Definition
- DNA methylation is a biological process in which methyl groups are added directly to the DNA molecule.
- It is an epigenetic mechanism involving the addition of a methyl (–CH₃) group to DNA, which often modifies gene function and influences gene expression without altering the DNA sequence.
- The most widely characterized form of DNA methylation is the covalent addition of a methyl group to the 5-carbon of the cytosine ring, producing 5-methylcytosine (5-mC).
- 5-methylcytosine is informally referred to as the “fifth base” of DNA due to its functional significance.
- The added methyl groups project into the major groove of the DNA helix, where they can inhibit transcription by interfering with transcription factor binding.
- In human DNA, 5-methylcytosine constitutes approximately 1.5% of the total genomic DNA.
- During early development, DNA methylation is typically erased during zygote formation and then re-established in the embryo around the time of implantation.
- DNA methylation is a fundamental component of chromatin structure and is usually found within CpG dinucleotide contexts.
- Research has demonstrated that DNA methylation plays a crucial role in the regulation of gene expression.
- These methylation modifications tend to occur at specific genomic locations, and their distribution varies among different species.
- DNA methylation has been shown to be a vital contributor to a wide range of cellular processes.
- Abnormal or aberrant methylation patterns have been linked to several human diseases.
- Historically, DNA methylation was discovered in mammals around the same time DNA was identified as the genetic material.
- In 1948, Rollin Hotchkiss first identified a modified form of cytosine in calf thymus DNA preparations using paper chromatography.
- He hypothesized that this modified fraction was 5-methylcytosine because it separated from cytosine in a manner similar to how thymine (methyluracil) separates from uracil.
- Hotchkiss further suggested that this modified cytosine occurred naturally within DNA.
- Although many researchers initially proposed that DNA methylation might regulate gene expression, definitive evidence did not emerge until the 1980s.
- Studies conducted during the 1980s demonstrated its involvement in gene regulation and cell differentiation.
- DNA methylation is now widely recognized, in coordination with other regulatory mechanisms, as a major epigenetic factor influencing gene activity.
Principle
- Although virtually all cells within an organism contain the same genetic information, not all genes are expressed at the same time in every cell type.
- Different cell types selectively express specific sets of genes, leading to functional diversity despite having identical DNA sequences.
- In a broader context, epigenetic mechanisms are responsible for mediating these diverse gene expression profiles across various cells and tissues in multicellular organisms.
- These epigenetic mechanisms regulate gene activity without altering the underlying DNA sequence.
- One major epigenetic mechanism that directly involves chemical modification of DNA is known as DNA methylation.
- DNA methylation occurs through the addition of methyl groups to specific DNA regions, influencing gene expression.
- During organismal development, DNA methylation patterns across the genome undergo dynamic changes.
- These changes result from the combined processes of de novo DNA methylation, where new methylation marks are added, and demethylation, where existing methyl groups are removed.
- As development progresses, these methylation changes become more refined and cell-type specific.
- Consequently, differentiated cells acquire stable and unique DNA methylation patterns.
- These stable methylation patterns play a key role in regulating tissue-specific gene transcription and maintaining cellular identity.
(A) Within the cell nucleus, DNA is tightly wound around an octamer of highly basic histone proteins, forming a compact structure known as chromatin. Epigenetic modifications can take place either on the protruding histone tails or directly on the DNA through methylation.
(B) DNA methylation specifically occurs at cytosine bases, where a methyl group is added to the 5′ position of the pyrimidine ring by enzymes called DNA methyltransferases (DNMTs).
(C) Two major categories of DNMTs are responsible for establishing DNA methylation patterns. De novo DNMTs introduce methyl groups onto previously unmethylated cytosines, while maintenance DNMTs add methyl groups to hemimethylated DNA, ensuring that methylation patterns are preserved on the newly synthesized complementary strand during DNA replication.
Significance
- Most DNA methylation is essential for normal growth and development of an organism.
- Proper DNA methylation patterns are required for maintaining normal cellular functions.
- DNA methylation plays a very important role in several key biological processes.
- It is crucial for genomic imprinting, where gene expression depends on the parent of origin.
- DNA methylation is involved in X-chromosome inactivation, ensuring dosage compensation in females.
- It helps suppress the transcription of repetitive DNA elements within the genome.
- DNA methylation also prevents the transposition of mobile genetic elements, thereby maintaining genomic stability.
- When DNA methylation becomes dysregulated, it can disrupt normal gene regulation.
- Abnormal methylation patterns have been linked to the development of diseases, including cancer.
- DNA methylation occurring in different genomic regions can exert different effects on gene activity.
- These effects depend on the underlying genetic sequence and the specific location of methylation within the genome.
Control
- The addition of methyl groups to DNA is tightly regulated at multiple levels within the cell.
- This process is carried out by a specific family of enzymes known as DNA methyltransferases (DNMTs).
- DNA methyltransferases catalyze the transfer of methyl groups to DNA, establishing methylation marks.
- Three major DNMT enzymes—DNMT1, DNMT3a, and DNMT3b—are essential for the establishment and maintenance of DNA methylation patterns.
- DNMT1 primarily maintains existing DNA methylation patterns during DNA replication.
- DNMT3a and DNMT3b are mainly responsible for de novo DNA methylation, creating new methylation marks during development and differentiation.
- In addition to these core enzymes, two other related enzymes, DNMT2 and DNMT3L, are also present.
- DNMT2 and DNMT3L have more specialized functions and play supportive or regulatory roles in DNA methylation-related processes.
References
- What Is Epigenetics. DNA Methylation. Available from: WhatIsEpigenetics.com
- Nature Education (Scitable). The Role of Methylation in Gene Expression.
- National Center for Biotechnology Information (NCBI). PMC3521964.
- National Center for Biotechnology Information (NCBI). PMC3174260.
- Epigenie. Important DNA Methylation Factors and Key Epigenetic Players.
