The phenomenon of cell type-specific DNA methylation has received much attention
in recent years and a number of DNA methylation differences have been described
between cells of the immune system. Of particular interest when studying DNA
methylation are CpG islands (CGIs) which are distinct from the rest of the genome
due to their elevated CpG content, generally unmethylated state and promoter
association. In the instances when they become methylated this is associated with
gene repression although it is unclear the extent to which differential methylation
corresponds to differential gene expression. I have used an immune system model to
assess the role of CGI methylation and the role of the methylation reader MBD2 in
regulation of gene expression.
A relatively small number of DNA methylation differences were seen between
immune cell types with the most developmentally related cells showing the fewest
methylation differences. Interestingly, the vast majority of CGI-associated cellspecific
methylation occurred at intragenic CGIs located, not at transcription start
sites, but in the gene body. Increased intragenic CGI methylation tended to associate
with gene repression, although the precise reason for this remains unclear. Most
differentially methylated CGIs were depleted for the active chromatin mark
H3K4me3 regardless of their methylation state but some of these were associated
with the silencing mark H3K27me3 when unmethylated. These findings suggest that
intragenic CGIs are a distinct class of genomic element particularly susceptible to
cell type-specific methylation. I also looked at the effect of removing the methyl-
CpG binding domain protein MBD2 from immune system cells. Immune cells from
Mbd2-/- mice showed a number of previously uncharacterised phenotypes as well as
a number of differences in gene expression compared to wild-type animals. Most of
these genes increased their expression in the absence of MBD2 consistent with
MBD2’s role as a transcriptional repressor and Mbd2-/- Th1 cells showed increases
in histone H3 acetylation compared to wild-type Th1 cells. This work provides an
insight into the role played by cell-specific CGI methylation and MBD2 in regulating
gene expression