1 Introduction
1.1 Epigenetics
Every human cell contains a fascinating 3 m long string of DNA that is tightly coiled
around repeating histone octamers, together called chromatin. Chromatin can be
packaged lightly, as is the case in actively transcribed DNA regions, or tightly,
leading to gene silencing by a decrease in DNA accessibility [1]. Variability in DNA
packaging, tightly or lightly, is mostly the result of differences in posttranslational
modification (PTM) of histones and is an important requisite for cell-specific gene
expression [2]. Numerous histone residues can be modified in a variety of ways,
including ubiquitination, phosphorylation, acetylation, and methylation, each having
their own specific effect [3]. Histone acetylation only occurs on lysine residues,
while both lysine and arginine are methylated. Lysine and arginine are positively
charged at physiological pH and are present in the N-terminal DNA-binding tail of
histones. Acetylation is thought to facilitate transcriptional activation either by
neutralization of the ionic interaction between the tail and DNA or by forming a
binding site for chromatin remodeling proteins [4]. Methylation is similarly associated with transcriptionally active genes, although this highly depends on the specific
lysine or arginine residues that are methylated and to what extent. Methyl marks are
furthermore a binding site for a number of chromatin-modifying proteins [5]. The
ability to influence gene expression through the modification of histones raises the
question if and how such modifications are being passed down to daughter cells
during replication to maintain similar gene expression patterns, which is the main
topic of epigenetics. All epigenetic mechanisms together provide an important
explanation of how cells with the same DNA are able to differentiate into distinct
cell lines.
1.2 Epidrugs
An important area of research centers on the enzymes that install and remove the
mentioned PTMs on histones. Such enzymes can be considered to be the principal
executors of epigenetic mechanisms. Being highly dynamic in nature, PTMs are not
only regulated in a cell-specific but also in a time-specific manner, in turn turning
many different genes on or off over the course of a cell cycle. The crucial consequence
of this discovery is that gene expression can directly be controlled at any point in time
by drugs that target the enzymes that carry out PTMs. To refer to their actions on
epigenetic processes, such drugs are often termed “epidrugs” [6]. “Epidrug” is,
however, not an all-encompassing name that only refers to an epigenetic component.
It becomes increasingly clear that also nonhistone proteins are targeted by enzymes
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
431
1.1 Epigenetics
Every human cell contains a fascinating 3 m long string of DNA that is tightly coiled
around repeating histone octamers, together called chromatin. Chromatin can be
packaged lightly, as is the case in actively transcribed DNA regions, or tightly,
leading to gene silencing by a decrease in DNA accessibility [1]. Variability in DNA
packaging, tightly or lightly, is mostly the result of differences in posttranslational
modification (PTM) of histones and is an important requisite for cell-specific gene
expression [2]. Numerous histone residues can be modified in a variety of ways,
including ubiquitination, phosphorylation, acetylation, and methylation, each having
their own specific effect [3]. Histone acetylation only occurs on lysine residues,
while both lysine and arginine are methylated. Lysine and arginine are positively
charged at physiological pH and are present in the N-terminal DNA-binding tail of
histones. Acetylation is thought to facilitate transcriptional activation either by
neutralization of the ionic interaction between the tail and DNA or by forming a
binding site for chromatin remodeling proteins [4]. Methylation is similarly associated with transcriptionally active genes, although this highly depends on the specific
lysine or arginine residues that are methylated and to what extent. Methyl marks are
furthermore a binding site for a number of chromatin-modifying proteins [5]. The
ability to influence gene expression through the modification of histones raises the
question if and how such modifications are being passed down to daughter cells
during replication to maintain similar gene expression patterns, which is the main
topic of epigenetics. All epigenetic mechanisms together provide an important
explanation of how cells with the same DNA are able to differentiate into distinct
cell lines.
1.2 Epidrugs
An important area of research centers on the enzymes that install and remove the
mentioned PTMs on histones. Such enzymes can be considered to be the principal
executors of epigenetic mechanisms. Being highly dynamic in nature, PTMs are not
only regulated in a cell-specific but also in a time-specific manner, in turn turning
many different genes on or off over the course of a cell cycle. The crucial consequence
of this discovery is that gene expression can directly be controlled at any point in time
by drugs that target the enzymes that carry out PTMs. To refer to their actions on
epigenetic processes, such drugs are often termed “epidrugs” [6]. “Epidrug” is,
however, not an all-encompassing name that only refers to an epigenetic component.
It becomes increasingly clear that also nonhistone proteins are targeted by enzymes
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
431