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Page 310 Yasin et al. J Transl Genet Genom 2020;4:307-19 I https://doi.org/10.20517/jtgg.2020.30

Figure 1. Schematic of chromodomain helicase DNA-binding (CHD) family protein structure. Subfamily 1 on the topmost row includes
CHD1 and CHD2. They both contain the defining tandem two chromodomains and two SNF-2 ATPase domains - which all CHD proteins
contain. They also contain a DNA-binding domain. Subfamily 2 on the middle row includes CHD3, CHD4 and CHD5, which in addition
to definitive chromo and SNF-2 ATPase domains, also contain tandem PHD motifs. Subfamily 3 on the bottom row includes the other
four CHD proteins (CHD6 to CHD9). Members of this group may have any combination of one or more SANT, BRK and conserved region
domains (denoted by dashed lines)

[24]
The chromodomains are capable of binding methylated DNA, RNA or histone tails while the SNF-2 like
ATP-dependent helicase domains confer enzymatic activity based upon ATP hydrolysis [25,26] . Thus, the CHD
proteins may be summarized as effectors of chromatin conformational change via directional binding based
upon methylation marks.

The nine human CHD proteins are further categorized into three groupings based upon their domain
architecture as follows [Figure 1]: CHD1 and CHD2 are prototypical, not distinguished by other motifs
but do contain a similar DNA-binding domain [25,26] , and CHD3, CHD4 and CHD5 do not contain DNA-
binding domains but do contain two plant homeodomain zinc-finger motifs (PHDs). PHDs are capable
[27]
of recognizing post-translational modifications of histone tails , conferring sophisticated specificity for
targeted chromatin remodeling. A significant example is the interaction between CHD3/4 and histone
deacetylase that is part of the potent Nucleosome Remodeling Deacetylase (NuRD) transcriptional regulator
[28]
complex . The remaining CHDs, CHD6, CHD7, CHD8 and CHD9, are a diverse grouping with several
additional domains, such as SANT, Brahma Kismet and conserved region, being recognized in their
structure. The specific functions of these domains are not yet completely understood.

Importantly, all CHDs are known to be ubiquitously expressed with the exception of CHD5, whose
[29]
expression is confined to neuronal tissue . A significant role in development for all CHDs has been
demonstrated by stem cell research, where function in cell lineage and fate determination as well as cellular
[16]
programming have been shown , indicating important roles for these proteins in human development and
function. Here, we will focus on CHD roles in neurodevelopmental disorders (NDDs). However, we first
begin by introducing NDDs and the contribution of epigenetic regulation in general to NDD causation.

EPIGENETICS IN NEURODEVELOPMENTAL DISEASE
Neurodevelopmental disorders
NDDs are a group of diseases that may be described as defects in the growth and development of the brain
or nervous system. According to the current clinical designations for mental disorders by the American
Psychiatric Association DSM-5 (Diagnostic and Statistical Manual, 5th edition, published in 2013), NDDs
include: intellectual disability (ID), autism spectrum disorder (ASD), attention deficit/hyperactivity disorder,
learning disorders, motor disorders and communication disorders. However, we note that from a molecular
biology perspective, especially considering a common epigenetic etiology, other disorders such as bipolar
disease and schizophrenia (SCZ) should be kept in mind as NDDs [30,31] . Among the NDDs, the most well