oxidized intermediates serve as epigenetic marks in their own right or if they are just
short-lived intermediates in the DNA demethylation pathway. Some evidence indicates that hm5C has some signaling properties, also because it is more prevalent than
the formyl and carboxyl derivatives [81]. In any case, the final product in the
oxidation cascade, 5-carboxylcytosine, could in theory be decarboxylated to reform
unmodified cytosine. However, a decarboxylase that is capable of decarboxylating
5-carboxylcytosine is yet to be identified. Known mechanisms to date show that the
oxidized versions of 5mC are diluted in a replication-dependent manner to regenerate unmodified cytosine or in the case of 5-formyl and 5-carboxylcytosine are
recognized and excised by enzymes involved in base excision repair mechanisms
[82, 83]. The first step in this process is to flip the oxidized base out of the DNA
double helix followed by cleavage of the N-glycosidic bond, which is catalyzed by
thymine DNA glycosylase [84]. This leaves a gap in the DNA while leaving the
sugar phosphate backbone intact. Other enzymes then refill the gap with an
unmodified cytosine.
Protein demethylation is a somewhat simpler process that nonetheless also starts
with oxidation [85]. However, in this case oxidation results in an unstable intermediate, a hemiaminal, which degrades to release formaldehyde and the thus
demethylated lysine or arginine residue. Similar to HDACs, lysine demethylases
(KDMs) come in various isoforms, and KDMs are grouped based on their dependency on either Fe(II) and 2-oxoglutarate or flavin [86–88]. In contrast, so far just
one enzyme, the Jumonji domain containing protein 6, is speculated to have arginine
demethylation activity in vivo [89]. The functionally opposing group of methyltransferases for both lysines and arginines is even larger and more diverse. Additionally, while acetyltransferases catalyze the addition of just one acetyl group to a lysine
residue, methyltransferases mono-, di-, or tri-methylate them and mono- or
di-methylate arginines [90]. The extent of methylation and the specific residues
involved dictate the functional outcome.
3.1 Cross Talk Between Acetylation and Methylation
An additional layer of complexity is added by the fact that PTMs can be linked
mechanistically by processes that are collectively termed “cross talk” [91]. As an
example, methylation of histone H3 on lysine 4 (H3K4) recruits acetyltransferases to
acetylate several other lysine residues of histone H3 [92]. Furthermore, the degree to
which H3K4 is methylated directly influences the extent of H3 acetylation [93]. As a
result, trimethylation of H3K4 is generally considered to be a marker of transcriptional activation. Additionally, methylation of H3K4 is known to inhibit DNA
methylation, thereby further ensuring transcriptional activation [94, 95]. Conversely,
DNA methylation decreases H3K4 methylation and H3 acetylation through a group
of proteins that specifically recognize and bind to methylated DNA and in turn
recruit a protein complex that contains HDACs and histone demethylases
[96, 97]. Cross talk thus not only occurs between histone modifications but also
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
441
short-lived intermediates in the DNA demethylation pathway. Some evidence indicates that hm5C has some signaling properties, also because it is more prevalent than
the formyl and carboxyl derivatives [81]. In any case, the final product in the
oxidation cascade, 5-carboxylcytosine, could in theory be decarboxylated to reform
unmodified cytosine. However, a decarboxylase that is capable of decarboxylating
5-carboxylcytosine is yet to be identified. Known mechanisms to date show that the
oxidized versions of 5mC are diluted in a replication-dependent manner to regenerate unmodified cytosine or in the case of 5-formyl and 5-carboxylcytosine are
recognized and excised by enzymes involved in base excision repair mechanisms
[82, 83]. The first step in this process is to flip the oxidized base out of the DNA
double helix followed by cleavage of the N-glycosidic bond, which is catalyzed by
thymine DNA glycosylase [84]. This leaves a gap in the DNA while leaving the
sugar phosphate backbone intact. Other enzymes then refill the gap with an
unmodified cytosine.
Protein demethylation is a somewhat simpler process that nonetheless also starts
with oxidation [85]. However, in this case oxidation results in an unstable intermediate, a hemiaminal, which degrades to release formaldehyde and the thus
demethylated lysine or arginine residue. Similar to HDACs, lysine demethylases
(KDMs) come in various isoforms, and KDMs are grouped based on their dependency on either Fe(II) and 2-oxoglutarate or flavin [86–88]. In contrast, so far just
one enzyme, the Jumonji domain containing protein 6, is speculated to have arginine
demethylation activity in vivo [89]. The functionally opposing group of methyltransferases for both lysines and arginines is even larger and more diverse. Additionally, while acetyltransferases catalyze the addition of just one acetyl group to a lysine
residue, methyltransferases mono-, di-, or tri-methylate them and mono- or
di-methylate arginines [90]. The extent of methylation and the specific residues
involved dictate the functional outcome.
3.1 Cross Talk Between Acetylation and Methylation
An additional layer of complexity is added by the fact that PTMs can be linked
mechanistically by processes that are collectively termed “cross talk” [91]. As an
example, methylation of histone H3 on lysine 4 (H3K4) recruits acetyltransferases to
acetylate several other lysine residues of histone H3 [92]. Furthermore, the degree to
which H3K4 is methylated directly influences the extent of H3 acetylation [93]. As a
result, trimethylation of H3K4 is generally considered to be a marker of transcriptional activation. Additionally, methylation of H3K4 is known to inhibit DNA
methylation, thereby further ensuring transcriptional activation [94, 95]. Conversely,
DNA methylation decreases H3K4 methylation and H3 acetylation through a group
of proteins that specifically recognize and bind to methylated DNA and in turn
recruit a protein complex that contains HDACs and histone demethylases
[96, 97]. Cross talk thus not only occurs between histone modifications but also
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
441