*2.2.4 Immunoglobulin-fold proteins*

This group, including NF-κB, IκB, NFAT, STAT, and p53, plays roles in transduction of biologically important signals to nuclei in response to cytokine-induced stimulation, viral infection, DNA-damage, and nutrients.

## *2.2.5 Leucine zipper proteins (bZIP)*

The bZIP family includes CREB/ATF, BACH1/2, and FOS/JUN. The FOS/JUN has been originally characterized as product of the proto-oncogene or immediate

**5**

*Introductory Chapter: Gene Expression Controlling System and Its Application to Medical Sciences*

early gene, which very quickly responds to neuronal stimulatory or cellular prolifer-

The zinc finger motifs, which could be separated into major two classes, (1) Cys4 and (2) Cys2His2, are the major motifs in numbers of TFs and DNA binding proteins

1.The Cys4-type proteins, including GRs, ERs, RARs, CREBBP, IGHMBP2, GATA, PPAR, are classified into zinc fingers ZZ (ZZZ), zinc fingers AN1 (ZFAND), and GATA zinc-finger domain-containing (GATAD) types.

2.The Cys2His2, or the zinc fingers C2H2 (ZNF) type, is the typical motif in the mammalian TFs. SP1, KLF4, KLF5, EGR3, and numbers of ZNF proteins

This group includes DBP, NF-1, HMGA, SMAD, and TBP. The RNase II and DNA glycosylases carry common motif, TBP-domain. The origin is thought to trace back to before the divergence of the three domains of life, bacteria, archaea, and

The classification implies that TATA-dependent initiation is not the standard but one of the site-specific transcriptions. For correct understanding of the cellular responses to differentiation/development-inducing signals, it should be examined

Water-insoluble factors, steroids, and vitamins will easily go through lipid bilayer to bind to nuclear receptors. On the other hand, water-soluble compounds bind to the membrane receptors to transfer signals into cells, causing prompt response to induce certain signal cascade [22] to enhance/suppress specific gene

*2.2.7 β-Structure (β-scaffold, β-sheet, and β-barrel) containing transcription* 

how the site-specific TFs could initiate transcription.

1. cyclic AMP (protein kinase A) pathway

**3. Stresses and signals that regulate gene expression**

*DOI: http://dx.doi.org/10.5772/intechopen.80676*

*2.2.6 Zinc finger motif containing proteins*

ation-inducing signals [19].

belong to this class.

*factors*

eukaryote [21].

expression as follows:

3.Wnt signaling

4.TGFβ signaling

5.JAK/STAT pathway

6.Toll-like receptor signaling

7.immunoreceptor signaling

2.MAP kinase pathways

[20].

*Introductory Chapter: Gene Expression Controlling System and Its Application to Medical Sciences DOI: http://dx.doi.org/10.5772/intechopen.80676*

early gene, which very quickly responds to neuronal stimulatory or cellular proliferation-inducing signals [19].

#### *2.2.6 Zinc finger motif containing proteins*

*Gene Expression and Control*

transcription.

neural tissues.

**2.2 The site-specific transcription factors**

have multiple characteristic motifs.

*2.2.2 Helix-turn-helix (HTH) proteins*

development of organisms.

*2.2.4 Immunoglobulin-fold proteins*

*2.2.5 Leucine zipper proteins (bZIP)*

*factors*

*2.2.1 Basic helix-loop-helix (bHLH) proteins*

are different in the distribution of the A-tracts, G-quadruplex, and CpG islands [4]. Given that most of the housekeeping genes are controlled by TATA or TATAlike elements, TATA-less promoters would be sensitive to the environments in response to various stresses. For example, some of the TATA-less promoters have DTIE binding sites [5]. The duplicated GGAA (TTCC) elements are frequently found near the transcription start sites (TSSs) of the human TATA-less promoters [6], implying that GGAA (TTCC) binding TFs contribute to the initiation of

Transcription mediator interplays with the transcription activator proteins and the GTFs to enable plasticity and flexibility of gene expression [7]. However, site-specific TF-mediated and TATA-independent transcription system should be investigated because it may control responses to stresses. The TFs are categorized by their amino acid sequences or domain structures according to TRANSFAC (www. edgar-wingender.de/huTF\_classification.html) database [8]. Some proteins might

The bHLH proteins contain a basic region and HLH motif, which is comprised of two α-helices separated by a loop [9]. The bHLH family, BMAL, C/EBP, CLOCK, c-MYC, MYOD, NPAS2, and SREBP1/2, regulates development of mesodermal and

The ETS, FOX, IRF, HOX, HSF, POU, and PAX proteins belong to the HTH protein group. The HTH domains are present in NANOG, OCT1, PDN, and FLI1 [10]. ETS family proteins [11–13], which bind to GGAA (TTCC)-core motifs, contain ETS domain [14]. They regulate oncogenesis, development, differentiation, and apoptosis. The homeodomain (HD) is classified into 16 major subclasses, including ANTP, HNF, POU, PRD, SIX/SO, and ZF [15]. The HD proteins, including OTFs [16], which consist about 15–30% of TFs in animals, regulate differentiation and

This group includes SOX [17] and NF-Y [18] proteins. They are thought to be the

This group, including NF-κB, IκB, NFAT, STAT, and p53, plays roles in transduction of biologically important signals to nuclei in response to cytokine-induced

The bZIP family includes CREB/ATF, BACH1/2, and FOS/JUN. The FOS/JUN has been originally characterized as product of the proto-oncogene or immediate

*2.2.3 High-mobility group (HMG) proteins and heteromeric CCAAT-binding* 

key TFs to regulate differentiation of cells, development of organs, and aging.

stimulation, viral infection, DNA-damage, and nutrients.

**4**

The zinc finger motifs, which could be separated into major two classes, (1) Cys4 and (2) Cys2His2, are the major motifs in numbers of TFs and DNA binding proteins [20].


## *2.2.7 β-Structure (β-scaffold, β-sheet, and β-barrel) containing transcription factors*

This group includes DBP, NF-1, HMGA, SMAD, and TBP. The RNase II and DNA glycosylases carry common motif, TBP-domain. The origin is thought to trace back to before the divergence of the three domains of life, bacteria, archaea, and eukaryote [21].

The classification implies that TATA-dependent initiation is not the standard but one of the site-specific transcriptions. For correct understanding of the cellular responses to differentiation/development-inducing signals, it should be examined how the site-specific TFs could initiate transcription.

#### **3. Stresses and signals that regulate gene expression**

Water-insoluble factors, steroids, and vitamins will easily go through lipid bilayer to bind to nuclear receptors. On the other hand, water-soluble compounds bind to the membrane receptors to transfer signals into cells, causing prompt response to induce certain signal cascade [22] to enhance/suppress specific gene expression as follows:


Cells are continuously receiving stresses, which are, for example, temperature, lights and radiations, proton and ionic gradient, nutrients, and pathogens, including bacteria and viruses. Therefore, responses to these stresses are essential for life [23]. The stress-induced signals will be converted to cellular responses, including secretion, gating ion channels, cellular behavior, proliferation, differentiation, senescence, apoptosis, and the development of organs. Some of the signals cause epigenetic changes or affect transcription of specific genes. We should remember that DNA methylations are required for setting accurate TSSs [24]. The epigenetic modification of DNAs, such as methylation, acetylation, and phosphorylation, and poly(ADPribosyl)ation, is dependent on the substrate molecules, S-adenosyl methionine, acetyl-CoA, ATP, and NAD+ , respectively [25]. They are the metabolites that we have learned from textbooks in biological chemistry. These molecules are so essential and indispensable for living things that they must be obtained from metabolism of nucleic acids, amino acids, lipids, and carbohydrates. Not only the epigenetic regulation, but also transcription is dependent on nutrients or the metabolites. For example, AMPK-FOXO pathway plays a role as a nutrient sensor to affect gene expression [26]. The AMPK has been shown to regulate NADPH homeostasis during energy stress [27]. Increased NAD+ /NADH ratio serves as a metabolic switch for transcription of the *BRCA1* gene [28]. The transcriptional corepressor protein, CtBP1, which possesses an NADH binding domain [29, 30], is one of the candidates that play a role in the NAD+ / NADH ratio-dependent transcription system. Importantly, several human DNArepair-factor encoding gene promoters respond to natural compound *trans*-resveratrol (Rsv), which upregulates NAD+ /NADH ratio in HeLa S3 cells [31], implying that expression of the DNA-repair associated genes is partly regulated by metabolic state.

### **4. Analyses of gene expression in human diseases**

The next-generation sequencing (NGS) analysis greatly contributed for the identification of specific genetic errors [32]. Somatic mutations on cancer driver genes have been identified [33, 34] and the statistical data contribute for the prediction or diagnosis of cancer. In search of biomarkers and cancer-causing factors, transcriptome analyses have been applied on model animals and clinical samples from patients, gradually unveiling mechanisms of the cancer progression. Hot spot somatic mutations are observed in the promoter regions of the human cancer genomes [35]. Binding of the TFs on the promoter could regulate mutation rate to modulate both transcription and DNA-repair systems [36]. In melanomas, such mutations are highly found on the human *TERT* gene promoter [37, 38]. Thus, cancer-causing mutations are not only present in the protein-coding genes, but also in the gene expression regulatory regions.

Transcriptome analysis does not only contribute to the diagnosis or prognosis of cancer but also other human diseases. For example, different gene expression patterns have been shown in autism [39], type 2 diabetes (T2DB) [40], schizophrenia [41], and neurodegenerative disease, including Alzheimer's disease (AD) [42, 43]. Accumulation of repeat containing RNAs in aberrant foci in nucleus has been observed in Huntington disease, muscular dystrophy, and amyotrophic lateral sclerosis (ALS) [44]. The noncoding RNAs (ncRNAs), the long ncRNAs (lncRNAs), or long intergenic ncRNAs (lincRNAs) play essential roles in epigenetic regulation and in conversion of the nuclear structures [45]. Therefore, not only the protein encoding genes but also the ncRNAs are thought to be involved in the pathogenesis [46–48]. The lncRNAs control chromatin structure and nuclear architecture to regulate transcription in eukaryotic cells [49]. Thus, it is very important to explore how the lncRNAs are being regulated. Conversely, introduction of lncRNAs could be applied for treatment of specific diseases.

**7**

follows:

*Introductory Chapter: Gene Expression Controlling System and Its Application to Medical Sciences*

Varieties of human diseases could be caused by the dysregulation in transcription of either or both protein-encoding genes and ncRNAs. Although, it has not been examined if alteration in transcription is applicable for treatment of the presently intractable diseases, it will be possible in principle. A number of natural and chemical compounds could affect gene expression. Alternatively, transcription could be modulated by the introduction of expression vectors, which express specific TFs in the target cells. In an effort to reach that goal, we have to develop

Natural compounds or phytochemicals could be applied on treatment of specific diseases. Some of them affect the JAK/STAT signaling pathway that activates cell cycle/proliferation-controlling factor-encoding gene expression [50]. Sulforaphane

These observations imply that phytochemicals could be used for therapeutic use. To minimize side effects, how the molecular mechanisms affect transcription should be elucidated. Next-generation therapies for intractable human diseases might be enabled by introduction of TF-expression vectors or by editing specific site(s) of the genome. Additionally, nucleotides or nucleic acid-based pharmaceutical compounds might be developed to ameliorate profile or status of gene expres-

**5.2 Dysregulation in transcription might cause aging-related diseases**

Indeed, aging is not a disease in principle. However, incidences of specific diseases are increased according to the process, for example, arteriosclerosis, cancer, sarcopenia, and neurodegenerative diseases, including AD. The causations of aging have been studied and discussed at the cellular level and they could be classified as

Aging is thought to be accelerated by the accumulation of damage on chromosomal DNAs. This hypothesis is supported by the identification of responsive genes for premature aging, for example, LMNA, WRN, ATM, and SRPTN [61, 62]. Therefore, the aberrances in the nuclear architecture and DNA repair systems may cause premature aging. Cellular senescence is generally accompanied with the shortening of telomeres [63]. This is consistent with the observations that short-

**5. Application of transcriptional control on medical sciences**

reliable methods to deliver genes into abnormal or lesion cells.

cleaving enzyme 1-encoding *BACE1* gene expression [60].

*5.2.1 Genome instability, including telomere shortening*

ened telomeres cause genomic instabilities.

sion in dysregulated cells.

**5.1 Natural and the derivative compounds that regulate transcription**

targets Nrf2 [51], which responds to oxidative stress, implying that it can be applied for the treatment of metabolic syndromes [52]. Tannic acid, coumarins, and chalcones suppress 12-*O*-tetra decanoylphorbol-13-acetate (TPA)-induced HIV promoter activity in human Jurkat cells [53]. Rsv induces promoter activities of DNA-repair factor-encoding genes, including *TP53*, *WRN*, *TERT*, and *HELB* [54–56]. The GGAA-containing motif and the GC-box have been suggested to play an essential role in the response. Vitamin E and the related compounds, including tocotrienols, activate transcription by binding to estrogen receptors [57] but inactivate NF-κB activity [58]. Curcumin, which is a diferuloylmethane from the Indian spice turmeric, also targets NF-κB and AP1 to affect survival and proliferation of cells [59], might be applied on the suppression of the *APP* and the beta-site APP

*DOI: http://dx.doi.org/10.5772/intechopen.80676*

*Introductory Chapter: Gene Expression Controlling System and Its Application to Medical Sciences DOI: http://dx.doi.org/10.5772/intechopen.80676*
