1. Introduction The gene expression programs and chromatin regulationthat establish and maintain specific cell states in humans are controlled bythousands 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 ofdiseases like cancer and inflammations.
Here we review recent advances in ourunderstanding of transcriptional regulation and discuss how these have providednew insights into transcriptional misregulation in disease andgive us a prospective for gene therapeutic (Wan, L. et al., 2017).In this review the therapeutic potential of geneexpression process will be discussed also we will focus on chromatindependencies at gene promoters and distal regulatory elements, as we discussthat cancer may be caused by chromatin regulators we will discuss a prospectivemethods to inhibit the bad expression of chromatin by using certain inhibitorsthat may lead to cures for cancer, also we will mention some drugs thatselectively killing cancer cells and inflammations and keep housekeeping genesintact (Baranello, L., et al 2016). 1.1 Chromatin regulators andinducible gene expression.
Remodeling is a terminology thatmean a change in chromatin built to make DNA (condensed DNA) available fortranscriptional factors such as regulatory transcriptional factors. The keypoint here is that scientist are trying to find the clue how to epigenetic canserve in cancer treatment, the previous including DNA and histone methylationand acetylation by using specific enzymes (HATs), deacetylases, methyltransferases (Galbraith, M. D. et al.
, 2013). And kinases, thechromatin bind with ATP molecules to make a complex called chromatin ATP-dependentcomplex that affect the nucleosomes by ejecting or restructure the nucleosomes.Epigenetic has significant effect on chromatin regulation and remodeling, as aresult all these regulation process have big effect on many biological process,oogenesis, apoptosis and gene replication maintaining process, pluripotency andseparation of chromosomes. Many Human diseases are found to be associated withAberrations in chromatin remodeling proteins, diseases such as cancer withdifferent types and shapes. So the main goal is to alter the chromatinremodeling pathways and that open wide hope for cancer treatment for severalcancer types. (Yamaguchi, Y. et., al.
2009). 2. Chromatin regulators in cancerChanges in the pattern of gene expression play animportant role in allowing cancer cells to acquire their hallmarkcharacteristics, while genomic instability enables cells to acquire geneticalterations that promote oncogenesis (Baranello, L.
et al., 2016).Genomic stability and maintenance mainly controlled by chromatin regulation andtranscription. Furthermore many studies have been implemented on how repeatedmutations in genes that encoded by regulatory factors of chromatin and histonicprotein in many types of cancers that affect people, and regards as a majormediators in tumors (solid or hematological). We are trying to increase ourunderstanding the role of chromatin in cancer, many factors should beinvestigated (histone point mutations, enhancers, changes in heterochromatinregulatory factors (Erb, M. A.
et al., 2017). The following figure (figure 1) showtwo broad classes of signal-responsive promoters.Figure 1.
Transcription of inducible genes and itsregulation (Marazzi et al., 2017).Solid tumors have different signaling pathways.Deregulation of receptor tyrosine kinases that activate PI3K–AKT and RAS–ERK signaling37 results in unrestrained RAS activation, which induces silencing of tumorsuppressor genes through promoter DNA methylation38. RAS also induces chromatinremodelling at a subset of enhancers and super enhancers and increases histone3 lysine 27 acetylation (H3K27ac) and BRD4 recruitment through the activity ofthe pioneer transcription factor GATA4 (REF. 39) (Erb, M. A.
et al., 2017).PTEFB is rolled by BRD4 to induce a unique transcription elongation, so bothBRD4 and PTEFB are very important for inducible genes after that mitogenicstimulation occurs. Figure 2 show the Remodellers that is clear that BRD4 hasan significant domination on MYC-dependent transcription activation inchromatin and genes after stimulation of serum (Kwak, Y. T. et al., 2010). Figure 2.
Remodellers (Marazzi et al., 2017).2.1 Chromatin features ofinducible genesTranslation and transcription ofDNA genes known as gene expression this process give specific amount ofresulting expressions in continuous steps. The previous process is wellcontrolled in every step of transcriptional, degradation and modification (Baillat,D. et al., 2005). When we are talking about regulation in term of geneexpression we should remember that regulation occurs at epigenetic and geneticprocess.
The different between genetic regulation and epigenetic regulationthat the first one is about a direct process between transcriptional factorsbut in epigenetics the alteration is not direct but it is about alteraccessibility of genes and transcriptional factors and this alteration ishelped by chemical modification of chromatin. Nucleosome is the basic unit ofDNA chromatin like beads in string, so DNA consist the strind but beads isconsist of protein-DNA complex, all that structure is called Nucleosome whichconsist 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-translationalmodifications, these modification affect the tail of histones (Chen, F. X. etal.
, 2015). 3. Epigenetic therapiesWhen we are talking aboutepigenetics is the same when we are talking about changing computer softwarewithout doing anything with hardware, and those changes are heritable so sonsthat reflected in gene expression, many researches focus on how epigeneticsaffect cancer initiation and development and how we can get betterunderstanding for epigenetic and cancer that open new methods to eradicatedifferent types of cancer (Stadelmayer, B. et al. 2014).May we can reverse the effect ofgene expression in cancer in different words; by epigenetics there are a chanceto change the expression of bad genes without do anything with the structuremethylation od DNA mean deactivating of genes and acetylation mean activationof the genes so that mean we can inactivate some gene expression to deleteoncogenes (Squazzo, S.
L. et al., 2002).3.1 Combining epigenetic therapy andimmunotherapyIn the past many methods are doneby scientist toward cancer therapy and help humanity but in recent years cancermanagement is appear to be done in immunotherapy methods to be the best routeto follow, but immunotherapy is not effective with skin cancer melanoma, so inthis case different strategy should be followed (Yamaguchi, Y. et al., 1999).Nowadays many epigenetic cancer drugs are developing such drugs include DNAmethyltransferase inhibitors that may increase expression in cancer cells inother side DNA demethylation may inhibit cancer genes to prevent harm topeoples, and demethylationmay induce T lymphocytes to make a check point forcancer cells when occur.
Scientist put huge effort to make different clinicaltrials that compine immune therapy and epigenetics (Galbraith, M. D. et al.
,2013).4. Conclusion and future perspectivesThe chromatin shape change bymultiple signals integrating inflammatory and oncogenic stimuli and thischanges do not affect housekeeping genes, also many factors should beconsidered as of chromatin topology to understand the whole picture of theregulation of genes expression. 3D interaction should be studycarefully of induced genes after cancer or inflammation and further researchsteps should be taken to complete our understanding of chromatin dependenciesDevelopment of novel small-molecule inhibitors to target additional chromatinregulators will certainly help to close the knowledge gap in the near future.
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