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[16]
critical regulators of cellular processes such as proliferation, stem cell inactivity and cell fate determination .
Moreover, CHD proteins are associated with a wide variety of human diseases, though we focus here only on
the role of CHD proteins and neurodevelopmental disease. We begin by detailing chromatin and chromatin
remodeling complexes below.

CHROMATIN AND CHROMATIN REMODELERS

Chromatin
Chromatin which is composed of DNA and the histone protein scaffold it is wound around, exists either as
condensed heterochromatin or as open euchromatin. Inside the nucleus, genomic DNA is tightly packaged
by winding a 146-nucleotide section around a histone protein octamer to form a “nucleosome”. The histone
octamer comprises two each of the histone proteins H2A, H2B, H3, H4 and also a linker histone H1. The
[17]
core octamer histones contain amino acid “tails” that may be modified by chemical moieties .
Nucleosomes restrict DNA accessibility to the transcription machinery. However, they are dynamic; the
DNA can become less or more tightly bound to the histone octamer, or the nucleosomes can become more
or less closely positioned to each other. These structural changes are thought to be directly linked to gene
transcription regulation, by making the DNA either more or less accessible to the transcription apparatus.
Regulation of gene expression can be further fine-tuned by nucleosomes through incorporating histone
variants and post-translational modifications to histone tails providing structural and hence functional
[18]
complexity .

As the naked DNA must be accessed for DNA replication, transcription and repair, these processes all
involve chromatin disruption and restoration, requiring dynamic changes in chromatin remolding. Thus
structural alteration in chromatin structure facilitates downstream gene expression specific to cellular
[19]
demand, and thereby holds significant importance in gene regulatory networks . The dynamism of
chromatin is a result of a symphony of changes that include remodeling of nucleosomes, modification of
histones, presence/absence of non-histone DNA-binding proteins and non-coding RNAs. These alterations
[20]
in chromatin structure are mostly carried out by chromatin remodelers .
Chromatin remodeling complexes
Chromatin remodelers are multiprotein complexes that catalyze nucleosome sliding (gliding of an octamer
[20]
across the DNA) and histone variant exchange (changing the conformation of nucleosomal DNA) . The
remodeling enzymes can bring about change by ATP hydrolysis between the histone-DNA contact within
the nucleosome. ATP-dependent chromatin remodelers utilize energy from ATP hydrolysis. They belong to
[21]
the superfamily 2 helicases and share a conserved core ATPase . ATP-dependent chromatin remodelers
are further classified into 4 separate families: SWI/SNF (switch/sucrose-non-fermenting), ISWI (imitation
switch), CHD (chromodomain helicase DNA-binding) and INO80 (inositol requiring 80). The distinction
between them lies in the exclusive domains that reside adjacent to their ATPase domain. Briefly, SWI/SNF
remodelers contain bromodomains, ISWI remodelers contain SANT-SLIDE modules, CHD remodelers
contain tandem chromodomains, and the INO80 family contains HAS (helicase SANT) domains. These
domains have distinctive roles in the regulation of ATPase activity, in recruiting remodelers, and for specific
[22]
histone modifications . Here, we will focus only on the CHD family.

CHD family
A number of proteins belonging to the chromodomain helicase DNA-binding family have been identified
across phyla. In humans, nine CHDs are known (CHD 1 to 9), four are recognized in Drosophila (dCHD-1,
dMi-2, Chd3 and Kismet) and one is known in yeast (yCHD1). They are well conserved, and distinguished
by the presence of two chromatin organization modifier (“chromo”) domains located in the N-terminal
[23]
region and two SNF-2-like ATP-dependent helicase domains positioned toward the center of the protein .