between histone modifications and other epigenetic processes like DNA methylation. Not surprisingly, cross talk between PTMs of many different proteins exists,
simply because lysines are found to be both acetylated and methylated, and these
modifications affect protein functionality in different ways. It is often not clear how
these different modifications compete with each other.
3.2 DNA Methylation in Asthma and COPD
There does not seem to be a clear association between DNA methylation levels and
the presence of COPD. While there are studies that suggest that DNA methylation
may be a biomarker of COPD [98], a genome-wide analysis of DNA methylation
using blood samples of 903 never and 658 current smokers from the general
population failed to show any significant association [99]. A systematic review of
six articles that assessed the association of COPD with DNA methylation also failed
to see consistency in the data [100]. Perhaps due to this lack of a clear link between
DNA methylation and COPD, no inhibitors of DNA methyltransferase have been
tested so far in in vivo models of COPD. Interestingly, the promotor of HDAC6 is
known to be hypomethylated in COPD [101], which may partly explain the elevated
HDAC6 expression seen in COPD and further point to treatment with HDAC6selective inhibitors.
In contrast, a large meta-analysis of DNA methylation in childhood asthma, using
data from more than 5,000 children, identified reduced DNA methylation levels in
14 distinct sites to be associated with asthma across childhood from ages 4 to
16 years [102]. Interestingly, whole blood DNA methylation profiles were strongly
driven by lower methylation within eosinophils, further highlighting the important
role of eosinophils in asthma. Additionally, the association was not found at birth,
suggesting that environmental factors, like allergen exposure, could be the main
cause of the observed change in the DNA methylation status. This possibility is
further supported by results from mouse models of asthma, which showed reduced
overall m5C and increased hm5C that correlated with a respective decrease in
DNMTs and increase in TET enzymes upon allergen exposure [103, 104]. This
indicates that DNMT activity limits asthma severity and thus that increasing DNA
methylation may be beneficial in asthma. In stark contrast, treatment with
azacitidine, a nonselective DNMTi, has been reported to reduce inflammation and
airway hyperreactivity in mice, possibly by increasing the numbers of regulatory T
cells [105]. Future research therefore needs to determine whether treatment of
asthma with DNMTi or with still to be developed DNA demethylase inhibitors
will be most beneficial.
442
M. R. H. Zwinderman et al.
simply because lysines are found to be both acetylated and methylated, and these
modifications affect protein functionality in different ways. It is often not clear how
these different modifications compete with each other.
3.2 DNA Methylation in Asthma and COPD
There does not seem to be a clear association between DNA methylation levels and
the presence of COPD. While there are studies that suggest that DNA methylation
may be a biomarker of COPD [98], a genome-wide analysis of DNA methylation
using blood samples of 903 never and 658 current smokers from the general
population failed to show any significant association [99]. A systematic review of
six articles that assessed the association of COPD with DNA methylation also failed
to see consistency in the data [100]. Perhaps due to this lack of a clear link between
DNA methylation and COPD, no inhibitors of DNA methyltransferase have been
tested so far in in vivo models of COPD. Interestingly, the promotor of HDAC6 is
known to be hypomethylated in COPD [101], which may partly explain the elevated
HDAC6 expression seen in COPD and further point to treatment with HDAC6selective inhibitors.
In contrast, a large meta-analysis of DNA methylation in childhood asthma, using
data from more than 5,000 children, identified reduced DNA methylation levels in
14 distinct sites to be associated with asthma across childhood from ages 4 to
16 years [102]. Interestingly, whole blood DNA methylation profiles were strongly
driven by lower methylation within eosinophils, further highlighting the important
role of eosinophils in asthma. Additionally, the association was not found at birth,
suggesting that environmental factors, like allergen exposure, could be the main
cause of the observed change in the DNA methylation status. This possibility is
further supported by results from mouse models of asthma, which showed reduced
overall m5C and increased hm5C that correlated with a respective decrease in
DNMTs and increase in TET enzymes upon allergen exposure [103, 104]. This
indicates that DNMT activity limits asthma severity and thus that increasing DNA
methylation may be beneficial in asthma. In stark contrast, treatment with
azacitidine, a nonselective DNMTi, has been reported to reduce inflammation and
airway hyperreactivity in mice, possibly by increasing the numbers of regulatory T
cells [105]. Future research therefore needs to determine whether treatment of
asthma with DNMTi or with still to be developed DNA demethylase inhibitors
will be most beneficial.
442
M. R. H. Zwinderman et al.