The gene expression programs and chromatin regulation
that establish and maintain specific cell states in humans are controlled by
thousands of transcription factors, cofactors and chromatin regulators such as bromodomain and extra-terminal domain
(BET) proteins, topoisomerases, protein arginine N-methyltransferases (PRMTs)
and cyclin-dependent kinases (CDKs) (Gardini, A. et al., 2014).
Misregulation of these gene expression programs can cause a broad range of
diseases like cancer and inflammations. Here we review recent advances in our
understanding of transcriptional regulation and discuss how these have provided
new insights into transcriptional misregulation in disease and
give us a prospective for gene therapeutic (Wan, L. et al., 2017).
In this review the therapeutic potential of gene
expression process will be discussed also we will focus on chromatin
dependencies at gene promoters and distal regulatory elements, as we discuss
that cancer may be caused by chromatin regulators we will discuss a prospective
methods to inhibit the bad expression of chromatin by using certain inhibitors
that may lead to cures for cancer, also we will mention some drugs that
selectively killing cancer cells and inflammations and keep housekeeping genes
intact (Baranello, L., et al 2016).
1.1 Chromatin regulators and
inducible gene expression.
Remodeling is a terminology that
mean a change in chromatin built to make DNA (condensed DNA) available for
transcriptional factors such as regulatory transcriptional factors. The key
point here is that scientist are trying to find the clue how to epigenetic can
serve in cancer treatment, the previous including DNA and histone methylation
and acetylation by using specific enzymes
(HATs), deacetylases, methyltransferases (Galbraith, M. D. et al., 2013).
And kinases, the
chromatin bind with ATP molecules to make a complex called chromatin ATP-dependent
complex that affect the nucleosomes by ejecting or restructure the nucleosomes.
Epigenetic has significant effect on chromatin regulation and remodeling, as a
result all these regulation process have big effect on many biological process,
oogenesis, apoptosis and gene replication maintaining process, pluripotency and
separation of chromosomes. Many Human diseases are found to be associated with
Aberrations in chromatin remodeling proteins, diseases such as cancer with
different types and shapes. So the main goal is to alter the chromatin
remodeling pathways and that open wide hope for cancer treatment for several
cancer types. (Yamaguchi, Y. et., al. 2009).
2. Chromatin regulators in cancer
Changes in the pattern of gene expression play an
important role in allowing cancer cells to acquire their hallmark
characteristics, while genomic instability enables cells to acquire genetic
alterations that promote oncogenesis (Baranello, L. et al., 2016).
Genomic stability and maintenance mainly controlled by chromatin regulation and
transcription. Furthermore many studies have been implemented on how repeated
mutations in genes that encoded by regulatory factors of chromatin and histonic
protein in many types of cancers that affect people, and regards as a major
mediators in tumors (solid or hematological). We are trying to increase our
understanding the role of chromatin in cancer, many factors should be
investigated (histone point mutations, enhancers, changes in heterochromatin
regulatory factors (Erb, M. A. et al., 2017).
The following figure (figure 1) show
two broad classes of signal-responsive promoters.
Figure 1. Transcription of inducible genes and its
regulation (Marazzi et al., 2017).
Solid tumors have different signaling pathways.
Deregulation of receptor tyrosine kinases that activate PI3K–AKT and RAS–ERK signaling
37 results in unrestrained RAS activation, which induces silencing of tumor
suppressor genes through promoter DNA methylation38. RAS also induces chromatin
remodelling at a subset of enhancers and super enhancers and increases histone
3 lysine 27 acetylation (H3K27ac) and BRD4 recruitment through the activity of
the pioneer transcription factor GATA4 (REF. 39) (Erb, M. A. et al., 2017).
PTEFB is rolled by BRD4 to induce a unique transcription elongation, so both
BRD4 and PTEFB are very important for inducible genes after that mitogenic
stimulation occurs. Figure 2 show the Remodellers that is clear that BRD4 has
an significant domination on MYC-dependent transcription activation in
chromatin and genes after stimulation of serum (Kwak, Y. T. et al., 2010).
Figure 2. Remodellers (Marazzi et al., 2017).
2.1 Chromatin features of
Translation and transcription of
DNA genes known as gene expression this process give specific amount of
resulting expressions in continuous steps. The previous process is well
controlled in every step of transcriptional, degradation and modification (Baillat,
D. et al., 2005). When we are talking about regulation in term of gene
expression we should remember that regulation occurs at epigenetic and genetic
process. The different between genetic regulation and epigenetic regulation
that the first one is about a direct process between transcriptional factors
but in epigenetics the alteration is not direct but it is about alter
accessibility of genes and transcriptional factors and this alteration is
helped by chemical modification of chromatin. Nucleosome is the basic unit of
DNA chromatin like beads in string, so DNA consist the strind but beads is
consist of protein-DNA complex, all that structure is called Nucleosome which
consist of eight complex units of histone proteins that have four cores (H2A,
H2B, H3 and H4) with roughly 147 bp of DNA wrapped around each octamer. Methylation,
acetylation, and phosphorylation are regards as post-translational
modifications, these modification affect the tail of histones (Chen, F. X. et
3. Epigenetic therapies
When we are talking about
epigenetics is the same when we are talking about changing computer software
without doing anything with hardware, and those changes are heritable so sons
that reflected in gene expression, many researches focus on how epigenetics
affect cancer initiation and development and how we can get better
understanding for epigenetic and cancer that open new methods to eradicate
different types of cancer (Stadelmayer, B. et al. 2014).
May we can reverse the effect of
gene expression in cancer in different words; by epigenetics there are a chance
to change the expression of bad genes without do anything with the structure
methylation od DNA mean deactivating of genes and acetylation mean activation
of the genes so that mean we can inactivate some gene expression to delete
oncogenes (Squazzo, S. L. et al., 2002).
3.1 Combining epigenetic therapy and
In the past many methods are done
by scientist toward cancer therapy and help humanity but in recent years cancer
management is appear to be done in immunotherapy methods to be the best route
to follow, but immunotherapy is not effective with skin cancer melanoma, so in
this case different strategy should be followed (Yamaguchi, Y. et al., 1999).
Nowadays many epigenetic cancer drugs are developing such drugs include DNA
methyltransferase inhibitors that may increase expression in cancer cells in
other side DNA demethylation may inhibit cancer genes to prevent harm to
peoples, and demethylationmay induce T lymphocytes to make a check point for
cancer cells when occur. Scientist put huge effort to make different clinical
trials that compine immune therapy and epigenetics (Galbraith, M. D. et al.,
4. Conclusion and future perspectives
The chromatin shape change by
multiple signals integrating inflammatory and oncogenic stimuli and this
changes do not affect housekeeping genes, also many factors should be
considered as of chromatin topology to understand the whole picture of the
regulation of genes expression.
3D interaction should be study
carefully of induced genes after cancer or inflammation and further research
steps should be taken to complete our understanding of chromatin dependencies
Development of novel small-molecule inhibitors to target additional chromatin
regulators will certainly help to close the knowledge gap in the near future.
Epigenetic drugs as a innovated
cures should be used carefully and evaluated at single-cell level specially on
tumors growth or metastasis, that give us a chance to test those drugs in
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