- Methylated cytosines are found primarily at CpG dinucleotides, but are also found at non-CpG sites.
   - Most 5mCs are highly conserved epigenetic marks and are mostly found at CpG sites, where 70-80% of cytosines are methylated.
   - If CpG sites located in a gene body are hypermethylated, gene expression is increased. 
   - If CpG sites located in promoters or enhancers are hypermethylated, these regions cannot be bound by transcription factors, leading to trasncriptional silencing.
- Non-CpG methylation is restricted to specific cell types.
   - e.g., pluripotent stem cells, oocytes, neurons, and glial cells.
   - Accumulation of methylation at non-CpG sites and CpG sites in neurons seems to be involved in development and disease etiology.

Methylation of CpG Sites

- Alterations in NR3C1 methylation can occur early in life as consequences of stress exposure and can persist up to adulthood. 
- Higher NR3C1 methylation levels are also those with enhanced vulnerability to develop BPD.
   - In adult rodent offspring of high compared to low maternal care, regions spanning the NR3C1 gene were differentially methylated and acetylated, highlighting that in the context of early life stress, alterations in gene-networks rather than in a single or few genes is involved.
   - In humans, increased methylation levels within the NR3C1 promoter region was reported in subjects that had a history of early life adverse events.
   - Significant association between NR3C1 methylation and self-injurious behavior/previous hospitalizations.
- Increased methylation of CpG sites within the NR3C1 gene may contribute to BPD aetiopathogenesis.

Methylation of NR3C1 Gene

DNA methylation is a common epigenetic signaling tool that cells use to regulate gene expression. It occurs by adding or removing a methyl group at the fifth carbon of the pyrimidine ring of cytosine to form 5-methylcytosine (5mC). Given the nature of this mechanism—wherein it can have a significant effect on cell development and differentiation—errors in methylation could give rise to a number of devastating consequences, including various diseases.

University of Minnesota - Twin Cities

Epigenetics involves genetic control by factors other than an individual's DNA sequence. Epigenetic changes can switch genes on or off and determine which proteins are transcribed. Unlike genetic changes, epigenetic changes are reversible and do not change your DNA sequence, but they can change how your body reads a DNA sequence.

Epigenetic Influence

Phillips, T. (2008) The role of methylation in gene expression. Nature Education, 1(1), 116. https://www.nature.com/scitable/topicpage/the-role-of-methylation-in-gene-expression-1070/

The role of methylation in gene expression

Jang, H. S., Shin, W. J., Lee, J. E., & Do, J. T. (2017). CpG and non-CpG methylation in epigenetic gene regulation and brain function. Genes, 8(6), 148. https://doi.org/10.3390/genes8060148

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