Biomedical Engineering Reference
In-Depth Information
occur. Two different kinds of enzymatic complexes mediate remodeling: ATP-
dependent chromatin-remodeling complexes, such as switching/sucrose nonfer-
menting (SWI/SNF), use ATP to change the position of specific nucleosomes or
to alter the three-dimensional structure of the nucleosome. The other enzymes,
including HATs, HDACs, kinases, and methyltransferases, modify the N-terminal
tails of the histone proteins, thereby influencing transcriptional activity in local
chromatin regions. In fact, the N-terminal histone tails are subject to multiple
posttranslational modifications, including acetylation, phosphorylation, methyla-
tion, ubiquitylation, and ADP ribosylation. In general, acetylated histone tails are
found in transcriptionally active regions of chromatin, while deacetylated histones
accumulate in transcriptionally repressed regions [64,81,82].
The acetylation of local histone tails can be an important step governing the
activation of NF-
stimulation is associated with
the acetylation of histone H4 in the granulocyte macrophage-colony stimulating
factor (GM-CSF) promoter [83,84]. Similarly, LPS stimulation leads to hyperacety-
lation of histones H3 and H4 in the promoters of the IL-8, to macrophage inflam-
matory protein (MIP)-1
κ
B target genes. For example, IL-1
β
α
, and IL-12p40 genes, and to acetylation of H4 in the
stimulation results in the hyper-
acetylation of H3 in the LTR of HIV [87] and promoter of the E-selectin gene in
endothelial cells [88]. These increased levels of H3 and H4 acetylation correlate with
increased recruitment of RNA polymerase II to these various transcription units and
an overall increase in gene expression [85,86,87]. Viral infection can also promote
the hyperacetylation of histones surrounding the NF-
NF-
κ
B-dependent IL-6 promoter [14,85,86]. TNF-
α
-
composite enhancer, thereby helping to mobilize the cellular antiviral defenses [89].
Importantly, high basal levels of histone H4 acetylation and fully accessible
κ
B-dependent interferon-
β
NF-
κ
B binding sites are characteristic of the promoter regions of NF-
κ
B regulated
genes that undergo rapid upregulation, among them I
, MIP-2, and manganese
superoxide dismutase (MnSOD). These genes appear to be preprogrammed for rapid
activation through appropriate epigenetic modifications of the surrounding chromatin
structure [86]. Thus, the different patterns of histone acetylation may determine the
speed with which transcription of different NF-
κ
B
α
B target genes is initiated. It is not
known whether these patterns occur in a cell-type-specific or stimulus-specific man-
ner or contribute to target gene specificity.
Conversely, impaired NF-
κ
B action is associated with HDAC-mediated histone
deacetylation. For example, glucocorticoids inhibit NF-
κ
B-dependent gene activa-
tion through deacetylation of key histone residues, either by facilitating the recruit-
ment of HDACs or by directly repressing HAT activity [83,84]. Similarly,
Drosophila
jun N-terminal kinase (JNK) inhibits the NF-
κ
κ
B pathway by recruiting dHDAC1 to
the promoters of various NF-
κ
B target genes [90]. In addition, p50 homodimers can
function as
B-specific repressors by recruiting HDAC-1-containing complexes or
SMRT-HDAC3 complexes, which likely promote histone deacetylation in regions
where these homodimers bind [14,61]. The phosphorylation state of p65 appears to
function as a switch that controls the association of NF-
κ
B with the cofactors
responsible for modifying histone acetylation in these conditions [14]. These findings
underscore how dynamic changes in the pattern of histone acetylation mediated by
HATs and HDACs help to regulate the expression of NF-
κ
κ
B target genes.
