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Page 308 Yasin et al. J Transl Genet Genom 2020;4:307-19 I https://doi.org/10.20517/jtgg.2020.30

and regulation can be controlled by a non-DNA sequence environment. Currently three main epigenetic
processes have gained prominence: DNA modification (mainly methylation), histone modification, and
[2]
chromatin remodeling. A fourth process termed RNA interference and associated RNA-based control
mechanisms are also now coming into focus. For the purposes of this review, we will focus only on chromatin
remodeling and specifically the role of the chromodomain protein family as chromatin remodelers. However,
chromatin remodeling does not occur as a stand-alone process. On the contrary, it is closely linked to, and
works in concert with, other epigenetic regulatory mechanisms. Therefore, we will define them briefly below.

Main types of epigenetic modifications
DNA modification
DNA modification refers to the process of adding/removing chemical moieties to/from the DNA sugar-
phosphate backbone, usually at the 5 carbon position of cytosine. The best known of these modifications
is DNA methylation; the addition or removal of methyl groups from the DNA backbone. It has been
best characterized in the context of cytosine-guanine (CpG) dinucleotides, and is catalyzed by DNA
[3]
methyltransferases . Cytosine methylation within gene promoters has been typically associated with
transcriptional repression: the presence of the methyl moiety alters the chemical stoichiometry and thus
directly obstructs the binding of transcription factors, and/or may also locally induce a repressive chromatin
[4,5]
structure that is nontolerant to transcription .

However, the relationship between DNA methylation and the regulation of gene expression is complex.
For example, “CpG methylation” can be positioned at non-CpG sites, particularly in neuronal cells , and
[6,7]
[5]
cytosine methylation may cause repression or activation of genes, depending on the context . Finally, DNA
[8]
methylation can also affect alternative splicing . Therefore, this complexity requires careful interpretation.
Recently, additional forms of DNA base modification have been recognized; DNA hydroxymethylation,
carboxylation and formylation are examples of other DNA modifications, albeit their roles are not yet well
[9]
defined.

Histone modification
A second type of epigenetic control process is the modification of the tails of histone proteins by adding or
removing chemical moieties. These moieties include, for example, methyl, acetyl, and sumoyl groups, among
others. Modification of histones tails are more varied, in that they occur at several positions along the tails of
different histones, and complicated, in that there can be more than one group added or removed at the same
position, and their effect on gene function can also be more nuanced compared to DNA modification.
[10]
For example, methylation of the 4th and 27th lysine can occur as mono-, di- or trimethylation. However,
H3K4me3 (trimethylation at the fourth lysine of histone 3) marks are mainly associated with activating
gene promoters while H3K27me3 (trimethylation at the 27th lysine of histone 3) marks are associated with
repressing regulatory regions [11,12] .

Chromatin regulation
Importantly, both DNA methylation and histone modifications are known to interact to regulate chromatin
[13]
structure and gene expression . This process takes place involving the action of large multi-protein
[14]
complexes called chromatin remodeling complexes . They contain, in addition to positioning factors,
key enzymes that directly control the regulation of gene expression, usually by catalyzing either DNA
or histone modification reactions. The enzymes may be classified as: chromatin writers (e.g., histone
methyltransferases and acetylases), erasers (e.g., histone demethylases and deacetylases), and readers (e.g.,
[15]
mainly chromodomain remodeling proteins) .
Chromatin readers include an important family of ATP-dependent DNA-binding proteins called
chromodomain helicase DNA-binding (CHD) proteins, which are the focus of this review. These proteins are