DNA Methylation

DNA methylation is a crucial epigenetic modification that regulates gene expression without altering the DNA sequence. It plays essential roles in gene silencing, cellular differentiation, genomic stability, and disease processes such as cancer.

How DNA Methylation Occurs
DNA methylation typically occurs at cytosine bases, specifically at CpG sites (where a cytosine is followed by a guanine in the DNA sequence). The process is catalyzed by enzymes called DNA methyltransferases (DNMTs), which transfer a methyl group (-CH₃) from S-adenosylmethionine (SAM) to the 5-carbon of the cytosine ring, forming 5-methylcytosine (5mC).

Biological Importance

  1. Gene Regulation: Methylation at promoter regions generally represses gene transcription by preventing transcription factor binding or recruiting repressive proteins.
  2. Genomic Imprinting: Certain genes are expressed in a parent-specific manner due to methylation patterns inherited from the mother or father.
  3. X-Chromosome Inactivation: In females, DNA methylation helps silence one of the two X chromosomes to balance gene dosage between sexes.
  4. Transposon Suppression: Methylation prevents the activation of transposable elements, protecting genomic integrity.
  5. Cell Differentiation and Development: Methylation patterns change as cells specialize, influencing which genes are turned on or off.

Reversibility and Disease Implications
DNA methylation is reversible, with demethylation enzymes (e.g., TET proteins) playing a role in removing methyl groups. Abnormal DNA methylation, such as hypermethylation of tumor suppressor genes or hypomethylation leading to genomic instability, is often associated with cancer and other diseases.

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Molecular Mechanism of DNA Methylation

  1. DNA Methyltransferases (DNMTs) and Methyl Group Transfer

    • The enzymes DNMT1, DNMT3A, and DNMT3B catalyze DNA methylation.

    • DNMT1 is responsible for maintenance methylation, copying existing methylation patterns onto newly synthesized DNA strands during replication.

    • DNMT3A and DNMT3B perform de novo methylation, establishing new methylation marks during development and differentiation.

  2. S-adenosylmethionine (SAM) as a Methyl Donor

    • DNMTs use S-adenosylmethionine (SAM) as a cofactor to donate the methyl group.

    • The methyl group is transferred to the 5th carbon of cytosine, producing S-adenosylhomocysteine (SAH) as a byproduct.

  3. CpG Islands and Their Regulation

    • CpG-rich regions, called CpG islands, are typically found in promoter regions.

    • In actively transcribed genes, CpG islands are usually unmethylated to allow transcription factor binding.

    • Methylation of CpG islands recruits proteins like MeCP2 (methyl-CpG-binding protein 2), which recruit histone deacetylases (HDACs) and chromatin remodeling complexes, leading to chromatin condensation and gene silencing.

  4. Methylation and Transcriptional Repression

    • Methylated cytosines block transcription factor binding directly.

    • Methylation recruits MBD (methyl-CpG-binding domain) proteins, such as MeCP2, which in turn recruit co-repressors like histone deacetylases (HDACs), leading to heterochromatin formation and gene silencing.

Demethylation and Reversibility

  1. Passive Demethylation

    • If DNMT1 is inhibited or dysfunctional, methylation marks are gradually lost during successive DNA replications.

  2. Active Demethylation via TET Enzymes

    • Ten-eleven translocation (TET) enzymes (TET1, TET2, TET3) oxidize 5mC into 5-hydroxymethylcytosine (5hmC), which can then be further processed into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC).

    • The modified cytosines can be removed by base excision repair (BER) via TDG (thymine DNA glycosylase), restoring an unmethylated cytosine.