The diverse roles of DNA methylation in mammalian development and disease

Greenberg MVC, Bourc’his D. The diverse roles of DNA methylation in mammalian development and disease. Nat Rev Mol Cell Biol. 2019 Oct;20(10):590-607. doi: 10.1038/s41580-019-0159-6. Epub 2019 Aug 9. PMID: 31399642.

Nature Reviews Molecular Cell Biology

DNA methylation of the 5mC is associated with transcriptional repression and through that repression affects genomic imprinting X chromosome inactivation, repressing transposons and germline-specific genes. The methylation enables a higher mutation rate as 5mC is deaminated to a thymine, which when paired with A, is not easily repaired. Most cancer types show a dysregulation of DNA methylation.

The mammalian genome undergoes major epigenetic reprogramming after fertilization and germline cell specification.

Cellular functions of DNA methylation

DNMT3A and DNMT3B are the two major de novo DNA methylation enzymes. They have a highly conserved methyltransferase domain and two chromatin reading domains.

The bodies of actively transcribed genes are enriched with DNA methylation, while active promoters are unmethylated. De novo methylation can occur in any sequence context, but only the methylation in CpG contexts are preserved through cell division by the methylation maintenance enzyme DNMT1 working with the E3 ubiquitin ligase UHRF1.

Demethylation is done by TET that oxidises methylated cytosine. Oxidised forms of C can promote demethylation during replication.

Gene bodies tend to be quite heavily methylated which is paradoxical since methylation makes mutagenesis more likely. It may be because it facilitates transcription elongation and co-transcriptional splicing. It may also repress intragenic cryptic promoters.

CpG-island promoter methylation

Most of mammalian promoters are CpG-islands that are rarely methylated. They are methylated in the cases on X-chromosome inactivation, genomic imprinting and in germline specific genes.

Genomic imprinting is when genes expression is controlled based on whether the gene was inherited from the father or mother. Germline-specific genes need to be repressed with the onset of somatic differentiation during implantation.

Retrotransposons

The main targets of DNA methylation are retrotransposons that occupy around half of the genomic space. Their expression is controlled by CpG-rich promoters whose methylation is necessary for silencing them. DNMT3C is a newly discovered de novo DNMT specifically working to control retrotransposons. DNA methylation also serves to inactivate retrotransposons through increased mutagenesis by deamination.

Methylation patterning in development

Reprogramming occurs first after fertilization where the embryo loses gamete-specific DNA methylation patterns. Then there is a gradual loss of methylation until the blastocyst stage. However, there remains substantial methylation after the global demethylation processes which could possibly imply the existence of intergenerational epigenetic inheritance or transgenerational epigenetic inheritance.

Sex-specific patterns of methylation are established in germlines. Sperm have 80% CpG methylation while oocytes have 50% methylation.

Methylation and disease

DNMT1 mutations are associated with neurological disorders like hereditary sensory autonomic neuropathy 1E with dementia and hearing loss. DNMT3B mutations are found in immunodeficiency diseases. Heterozygous, germline mutations in DNMT3A are associated with growth disorders of early prenatal onset. Somatic mutations of this gene are linked to adult cancers like acute myeloid leukaemia.

Demethylation gene mutations are also linked to cancers like AML through TET2 mutations.