CHROMATIN REMODELING

The term ATP-dependent chromatin remodeling, or simply chromatin remodeling,

refers to dynamic changes in the structure of chromatin that occur during the life of a
cell. These changes range from local alterations in the positioning of one or a few
nucleosomes to larger changes that affect chromatin structure over a longer distance.
Chromatin remodeling is carried out by ATP-dependent chromatin-remodeling
complexes, which are a set of diverse multiprotein machines that reposition and
restructure nucleosomes.

In eukaryotes, changes in nucleosome position and histone composition are key

features of gene regulation. The regulation of transcription depends not only on the
activity of regulatory transcription factors that influence RNA polymerase via TFIID and
mediator to turn genes on or off, but must also involve changes in chromatin structure
that affect the ability of transcription factors to gain access to and bind their target
sequences in the promoter region. If the chromatin is in a closed conformation,
transcription may be difficult or impossible. By comparison, chromatin that is in an
open conformation is more easily accessible to transcription factors and RNA
polymerase so that transcription can occur. Although the closed and open
conformations may be affected by the relative compaction of a chromosomal region,
researchers have recently determined that histone composition and the precise
positioning of nucleosomes at or near promoters often play a key role in eukaryotic
gene regulation.

Chromatin Remodeling Complexes Alter the Positions and Compositions

of Nucleosomes
One way to change chromatin structure is through ATP dependent chromatin
remodeling. In this process, the energy of ATP hydrolysis is used to drive a change in
the locations and/ or compositions of nucleosomes, thereby making the DNA more or
less amenable to transcription. Therefore, chromatin remodeling is important for both
the activation and repression of transcription.

The remodeling process is carried out by a protein complex that recognizes

nucleosomes and uses ATP to alter their configuration. All remodeling complexes have a
catalytic ATPase subunit that is similar to other motor proteins, called DNA
translocases , that move along the DNA. Eukaryotes have multiple families of
chromatin remodelers. Though their names may differ depending on the species,
common chromatin-remodeling complex. families are referred to as the SWI/SNF-
family, the ISWI- family, the INO80-family, and the Mi-2-family. The names of these
remodelers sometimes refer to the effects of mutations in genes that encode remodeling
proteins. For example, the abbreviations SWI and SNF refer to the effects that occur in
yeast when these remodeling enzymes are defective. SWI mutants are defective in
mating-type switching, and SNF mutations create a sucrose nonfermenting phenotype.

Remodeler Properties
All remodelers share five basic properties: (a) an affinity for the nucleosome, beyond
DNA itself; (b) domains that recognize covalentvhistone modifications; (c) a similar
DNA dependent ATPase domain, required for remodeling and serving as a DNA-
translocating motor to break histone-DNA contacts; (d ) domains and/or proteins that
regulate the ATPase domain; and (e) domains and/or proteins for interaction with other
chromatin or transcription factors. Together, these shared properties allow nucleosome
engagement, selection, and remodeling. However, distinctive targeting and tasks
require remodeler specialization.

How do chromatin remodelers change chromatin structure? Three effects are possible.
One result of ATP-dependent chromatin remodeling is a change in the location of
nucleosomes (Figure 1). This may involve a shift in nucleosomes to a new location or a
change in the relative spacing of nucleosomes over a long stretch of DNA. A second
effect is that remodelers may evict histones from the DNA, thereby creating gaps where
nucleosomes are not found (Figure 2). A third possibility is that remodelers may
change the composition of nucleosomes by removing standard histones and replacing
them with histone variants (Figure 3).

Mechanisms of ATP-dependent chromatin remodeling

 1) Change in nucleosome position

2) Histone eviction

3) Replacement with variant histones

Histone Variants Play Specialized Roles in Chromatin Remodeling

The five histone genes, which encode histones H1, H2A, H2B, H3, and H4, are
moderately repetitive. The total number of histone genes varies from species to species.
As an example, the human genome contains over 70 histone genes that have been
produced by gene duplication events during evolution. Most of the histone genes encode
standard histone proteins. However, a few have accumulated mutations that change the
amino acid sequence of the histone proteins. These are called histone variants. Among
eukaryotic species, histone variants have been identified for histone H1, H2A, H2B, and
H3 genes, but not for the H4 gene.

What are the consequences of histone variation? Research over the past two decades
has shown that certain histone variants play specialized roles in chromatin structure
and function. In all eukaryotes, histone variants are incorporated into a subset of
nucleosomes to create functionally specialized regions of chromatin. In most cases, the
standard histones are incorporated into the nucleosomes while new DNA is synthesized
during S phase of the cell cycle. Later, some of the standard histones are replaced by
histone variants via chromatin-remodeling complexes.

Table 1 describes the standard histones and a few histone variants that are found in
humans. A key role of many histone variants is to regulate the structure of chromatin,
thereby influencing gene transcription. Such variants can have opposite effects. The
incorporation of histone H2A.Bbd into a chromosomal region where a particular gene is
found favors gene activation. In contrast, the incorporation of histone H10 represses
gene expression. Although our focus in this chapter is on gene regulation, it is worth
noting that histone variants play other important roles. For example, histone cenH3,
which is a variant of histone H3, is found at the centromeres of each chromosome and
functions in the binding of kinetochore proteins. Histone cenH3 is required for the
proper segregation of eukaryotic chromosomes.

Other histone variants are primarily found at specialized sites in certain cells. Histone
macroH2A is found along the inactivated X chromosome in female mammals, whereas
spH2B is found at the telomeres in sperm cells. Finally, certain histone variants appear
to play a role in DNA repair. For example, histone H2A.X becomes phosphorylated
where a double-stranded DNA break occurs. This phosphorylation is thought to be
important for the proper repair of that break.