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Can genes that activate transcription factors also called be called transcription factors?

Can genes that activate transcription factors also called be called transcription factors?


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If the sole known function of a gene is to activate a transcription factor, would that gene also be considered a transcription factor, or is there a word for such genes that are further upstream on the transcription activation cascade?


Yes. For an example, see this list of targets of NF-kB (a transcription factor). Many other transcription factors are included there. As for a TF that does nothing except activate another, single TF? I don't know that those exist - TFs tend to modulate multiple genes.


From the wikipedia article on TFs:

In molecular biology and genetics, a transcription factor (sometimes called a sequence-specific DNA-binding factor) is a protein that binds to specific DNA sequences, thereby controlling the flow (or transcription) of genetic information from DNA to messenger RNA.

The nature of the gene affected is irrelevant, a protein is a transcription factor if it binds to a gene's promoter and regulates that gene's transcription. Whether the regulated gene also codes for a TF does not enter into it.


You need to re-write your question, it is ambiguous and your use of terms is incorrect… Assumption: by "activation" you mean "activation of transcription resulting in the expression of the transcription factor"

1) Transcription factors are proteins

2) Genes are comprised of DNA elements

A transcription factor can be involved in initiating the EXPRESSION of a transcription factor, whereafter that second distinct transcription factor initiates the EXPRESSION of another gene that encodes another transcription factor.

Answer: No, genes do not "activate" transcription factors*

*Unless you are proposing the philosophical question of whether the DNA binding domain itself, which endows the transcription factor with a state of being active duty (i.e. fulfilling its purpose as a transcription factor), and thus that purpose is fulfilled only when the DNA binds the the TF, then a DNA binding domain can indeed "activate" the TF… but I'm pretty sure this isn't what you're asking.


Transcription factor

In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. [1] [2] The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the right cell at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a coordinated fashion to direct cell division, cell growth, and cell death throughout life cell migration and organization (body plan) during embryonic development and intermittently in response to signals from outside the cell, such as a hormone. There are up to 1600 TFs in the human genome. [3] Transcription factors are members of proteome as well as regulome.

  • gene expression – the process by which information from a gene is used in the synthesis of a functional gene product such as a protein
  • transcription – the process of making messenger RNA (mRNA) from a DNA template by RNA polymerase
  • transcription factor – a protein that binds to DNA and regulates gene expression by promoting or suppressing transcription
  • transcriptional regulationcontrolling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA
  • upregulation, activation, or promotionincrease the rate of gene transcription
  • downregulation, repression, or suppressiondecrease the rate of gene transcription
  • coactivator – a protein (or a small molecule) that works with transcription factors to increase the rate of gene transcription
  • corepressor – a protein (or a small molecule) that works with transcription factors to decrease the rate of gene transcription
  • response element – a specific sequence of DNA that a transcription factor binds to

TFs work alone or with other proteins in a complex, by promoting (as an activator), or blocking (as a repressor) the recruitment of RNA polymerase (the enzyme that performs the transcription of genetic information from DNA to RNA) to specific genes. [4] [5] [6]

A defining feature of TFs is that they contain at least one DNA-binding domain (DBD), which attaches to a specific sequence of DNA adjacent to the genes that they regulate. [7] [8] TFs are grouped into classes based on their DBDs. [9] [10] Other proteins such as coactivators, chromatin remodelers, histone acetyltransferases, histone deacetylases, kinases, and methylases are also essential to gene regulation, but lack DNA-binding domains, and therefore are not TFs. [11]

TFs are of interest in medicine because TF mutations can cause specific diseases, and medications can be potentially targeted toward them.


Transcription factor

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Transcription factor, molecule that controls the activity of a gene by determining whether the gene’s DNA (deoxyribonucleic acid) is transcribed into RNA (ribonucleic acid). The enzyme RNA polymerase catalyzes the chemical reactions that synthesize RNA, using the gene’s DNA as a template. Transcription factors control when, where, and how efficiently RNA polymerases function.

Transcription factors are vital for the normal development of an organism, as well as for routine cellular functions and response to disease. Transcription factors are a very diverse family of proteins and generally function in multi-subunit protein complexes. They may bind directly to special “promoter” regions of DNA, which lie upstream of the coding region in a gene, or directly to the RNA polymerase molecule. Transcription factors can activate or repress the transcription of a gene, which is generally a key determinant in whether the gene functions at a given time.

Basal, or general, transcription factors are necessary for RNA polymerase to function at a site of transcription in eukaryotes. They are considered the most basic set of proteins needed to activate gene transcription, and they include a number of proteins, such as TFIIA (transcription factor II A) and TFIIB (transcription factor II B), among others. Substantial progress has been made in defining the roles played by each of the proteins that compose the basal transcription factor complex.

During development of multicellular organisms, transcription factors are responsible for dictating the fate of individual cells. For example, homeotic genes control the pattern of body formation, and these genes encode transcription factors that direct cells to form various parts of the body. A homeotic protein can activate one gene but repress another, producing effects that are complementary and necessary for the ordered development of an organism. If a mutation occurs in any of the homeotic transcription factors, an organism will not develop correctly. For example, in fruit flies (Drosophila), mutation of a particular homeotic gene results in altered transcription, leading to the growth of legs on the head instead of antenna this is known as the antennapedia mutation.

Transcription factors are a common way in which cells respond to extracellular information, such as environmental stimuli and signals from other cells. Transcription factors can have important roles in cancer, if they influence the activity of genes involved in the cell cycle (or cell division cycle). In addition, transcription factors can be the products of oncogenes (genes that are capable of causing cancer) or tumour suppressor genes (genes that keep cancer in check).


How Do Transcription Factors Work

Transcription factors are the proteins responsible for the regulation of gene expression. Generally, RNA polymerase should recognize and bind to the promoter for the initiation of transcription. Promoter is the region of DNA that initiates the transcription of a particular gene. In prokaryotes, RNA polymerase itself binds to the promoter region. However, in eukaryotes, RNA polymerase binds to the promoter with the help of some other transcription factors called basal (general) transcription factors.

Transcription factors bind to the sequences known as transcription factor binding sites found within the cis-regulator DNA sequences of the gene, upstream to the promoter. Upon binding, they either facilitate or prevent the binding of RNA polymerase to the promoter. The transcription factor binding site is called either as the enhancer or silencer. The enhancers turn the gene “on” while the silencers turn the gene “off”. The transcription factors that bind to the enhancers and activate the gene expression are known as activators. They help basal transcription factors and/or RNA polymerase to bind to the promoter. The action of activators is shown in figure 1.

The transcription factors that bind to the silencers and repress the gene expression are known as repressors. Repressors prevent the basal transcription factors and/or RNA polymerases from binding to the promoter. Though transcription factor binding sites are apart from the promoter region, the flexibility of the DNA strand allows the joining of both transcription factor binding sites and promoter regions to come together by forming a DNA loop.

Different types of genes are expressed in different types of tissues. This differential gene expression is achieved by means of transcription factors. These genes are composed of several enhancers or silencers.

Conclusion

Gene expression has to be regulated based on the requirements of the cell. Transcription factors are responsible for the regulation of gene expression. They bind either to the enhancer or silencer region, upstream to the promoter of the gene. The transcription factors that bind to the enhancer regions are known as activators, and those that bind to the silencers are known as repressors. Activators facilitate the binding of RNA polymerase to the promoter region while repressors prevent the binding of RNA polymerase to the promoter region.

Reference:

1. “Transcription factors.” Khan Academy, Available here.

Image Courtesy:

1. “Transcription Factors” By Kelvinsong – Own work (CC BY 3.0) via Commons Wikimedia


Contents

A DNA transcription unit encoding for a protein may contain both a coding sequence, which will be translated into the protein, and regulatory sequences, which direct and regulate the synthesis of that protein. The regulatory sequence before ("upstream" from) the coding sequence is called the five prime untranslated region (5'UTR) the sequence after ("downstream" from) the coding sequence is called the three prime untranslated region (3'UTR). [3]

As opposed to DNA replication, transcription results in an RNA complement that includes the nucleotide uracil (U) in all instances where thymine (T) would have occurred in a DNA complement.

Only one of the two DNA strands serve as a template for transcription. The antisense strand of DNA is read by RNA polymerase from the 3' end to the 5' end during transcription (3' → 5'). The complementary RNA is created in the opposite direction, in the 5' → 3' direction, matching the sequence of the sense strand with the exception of switching uracil for thymine. This directionality is because RNA polymerase can only add nucleotides to the 3' end of the growing mRNA chain. This use of only the 3' → 5' DNA strand eliminates the need for the Okazaki fragments that are seen in DNA replication. [3] This also removes the need for an RNA primer to initiate RNA synthesis, as is the case in DNA replication.

The non-template (sense) strand of DNA is called the coding strand, because its sequence is the same as the newly created RNA transcript (except for the substitution of uracil for thymine). This is the strand that is used by convention when presenting a DNA sequence. [5]

Transcription has some proofreading mechanisms, but they are fewer and less effective than the controls for copying DNA. As a result, transcription has a lower copying fidelity than DNA replication. [6]

Transcription is divided into initiation, promoter escape, elongation, and termination. [7]

Setting up for transcription Edit

Enhancers, transcription factors, Mediator complex and DNA loops in mammalian transcription Edit

Setting up for transcription in mammals is regulated by many cis-regulatory elements, including core promoter and promoter-proximal elements that are located near the transcription start sites of genes. Core promoters combined with general transcription factors are sufficient to direct transcription initiation, but generally have low basal activity. [8] Other important cis-regulatory modules are localized in DNA regions that are distant from the transcription start sites. These include enhancers, silencers, insulators and tethering elements. [9] Among this constellation of elements, enhancers and their associated transcription factors have a leading role in the initiation of gene transcription. [10] An enhancer localized in a DNA region distant from the promoter of a gene can have a very large effect on gene transcription, with some genes undergoing up to 100-fold increased transcription due to an activated enhancer. [11]

Enhancers are regions of the genome that are major gene-regulatory elements. Enhancers control cell-type-specific gene transcription programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes. [12] While there are hundreds of thousands of enhancer DNA regions, [13] for a particular type of tissue only specific enhancers are brought into proximity with the promoters that they regulate. In a study of brain cortical neurons, 24,937 loops were found, bringing enhancers to their target promoters. [11] Multiple enhancers, each often at tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and can coordinate with each other to control transcription of their common target gene. [12]

The schematic illustration in this section shows an enhancer looping around to come into close physical proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of CTCF or YY1), with one member of the dimer anchored to its binding motif on the enhancer and the other member anchored to its binding motif on the promoter (represented by the red zigzags in the illustration). [14] Several cell function specific transcription factors (there are about 1,600 transcription factors in a human cell [15] ) generally bind to specific motifs on an enhancer [16] and a small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern level of transcription of the target gene. Mediator (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (pol II) enzyme bound to the promoter. [17]

Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two enhancer RNAs (eRNAs) as illustrated in the Figure. [18] An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of transcription factor bound to enhancer in the illustration). [19] An activated enhancer begins transcription of its RNA before activating transcription of messenger RNA from its target gene. [20]

CpG island methylation and demethylation Edit

Transcription regulation at about 60% of promoters is also controlled by methylation of cytosines within CpG dinucleotides (where 5’ cytosine is followed by 3’ guanine or CpG sites). 5-methylcytosine (5-mC) is a methylated form of the DNA base cytosine (see Figure). 5-mC is an epigenetic marker found predominantly within CpG sites. About 28 million CpG dinucleotides occur in the human genome. [21] In most tissues of mammals, on average, 70% to 80% of CpG cytosines are methylated (forming 5-methylCpG or 5-mCpG). [22] Methylated cytosines within 5’cytosine-guanine 3’ sequences often occur in groups, called CpG islands. About 60% of promoter sequences have a CpG island while only about 6% of enhancer sequences have a CpG island. [23] CpG islands constitute regulatory sequences, since if CpG islands are methylated in the promoter of a gene this can reduce or silence gene transcription. [24]

DNA methylation regulates gene transcription through interaction with methyl binding domain (MBD) proteins, such as MeCP2, MBD1 and MBD2. These MBD proteins bind most strongly to highly methylated CpG islands. [25] These MBD proteins have both a methyl-CpG-binding domain as well as a transcription repression domain. [25] They bind to methylated DNA and guide or direct protein complexes with chromatin remodeling and/or histone modifying activity to methylated CpG islands. MBD proteins generally repress local chromatin such as by catalyzing the introduction of repressive histone marks, or creating an overall repressive chromatin environment through nucleosome remodeling and chromatin reorganization. [25]

As noted in the previous section, transcription factors are proteins that bind to specific DNA sequences in order to regulate the expression of a gene. The binding sequence for a transcription factor in DNA is usually about 10 or 11 nucleotides long. As summarized in 2009, Vaquerizas et al. indicated there are approximately 1,400 different transcription factors encoded in the human genome by genes that constitute about 6% of all human protein encoding genes. [26] About 94% of transcription factor binding sites (TFBSs) that are associated with signal-responsive genes occur in enhancers while only about 6% of such TFBSs occur in promoters. [16]

EGR1 protein is a particular transcription factor that is important for regulation of methylation of CpG islands. An EGR1 transcription factor binding site is frequently located in enhancer or promoter sequences. [27] There are about 12,000 binding sites for EGR1 in the mammalian genome and about half of EGR1 binding sites are located in promoters and half in enhancers. [27] The binding of EGR1 to its target DNA binding site is insensitive to cytosine methylation in the DNA. [27]

While only small amounts of EGR1 transcription factor protein are detectable in cells that are un-stimulated, translation of the EGR1 gene into protein at one hour after stimulation is drastically elevated. [28] Expression of EGR1 transcription factor proteins, in various types of cells, can be stimulated by growth factors, neurotransmitters, hormones, stress and injury. [28] In the brain, when neurons are activated, EGR1 proteins are up-regulated and they bind to (recruit) the pre-existing TET1 enzymes which are highly expressed in neurons. TET enzymes can catalyse demethylation of 5-methylcytosine. When EGR1 transcription factors bring TET1 enzymes to EGR1 binding sites in promoters, the TET enzymes can demethylate the methylated CpG islands at those promoters. Upon demethylation, these promoters can then initiate transcription of their target genes. Hundreds of genes in neurons are differentially expressed after neuron activation through EGR1 recruitment of TET1 to methylated regulatory sequences in their promoters. [27]

The methylation of promoters is also altered in response to signals. The three mammalian DNA methyltransferasess (DNMT1, DNMT3A, and DNMT3B) catalyze the addition of methyl groups to cytosines in DNA. While DNMT1 is a “maintenance” methyltransferase, DNMT3A and DNMT3B can carry out new methylations. There are also two splice protein isoforms produced from the DNMT3A gene: DNA methyltransferase proteins DNMT3A1 and DNMT3A2. [29]

The splice isoform DNMT3A2 behaves like the product of a classical immediate-early gene and, for instance, it is robustly and transiently produced after neuronal activation. [30] Where the DNA methyltransferase isoform DNMT3A2 binds and adds methyl groups to cytosines appears to be determined by histone post translational modifications. [31] [32] [33]

On the other hand, neural activation causes degradation of DNMT3A1 accompanied by reduced methylation of at least one evaluated targeted promoter. [34]

Initiation Edit

Transcription begins with the binding of RNA polymerase, together with one or more general transcription factors, to a specific DNA sequence referred to as a "promoter" to form an RNA polymerase-promoter "closed complex". In the "closed complex" the promoter DNA is still fully double-stranded. [7]

RNA polymerase, assisted by one or more general transcription factors, then unwinds approximately 14 base pairs of DNA to form an RNA polymerase-promoter "open complex". In the "open complex" the promoter DNA is partly unwound and single-stranded. The exposed, single-stranded DNA is referred to as the "transcription bubble." [7]

RNA polymerase, assisted by one or more general transcription factors, then selects a transcription start site in the transcription bubble, binds to an initiating NTP and an extending NTP (or a short RNA primer and an extending NTP) complementary to the transcription start site sequence, and catalyzes bond formation to yield an initial RNA product. [7]

In bacteria, RNA polymerase holoenzyme consists of five subunits: 2 α subunits, 1 β subunit, 1 β' subunit, and 1 ω subunit. In bacteria, there is one general RNA transcription factor known as a sigma factor. RNA polymerase core enzyme binds to the bacterial general transcription (sigma) factor to form RNA polymerase holoenzyme and then binds to a promoter. [7] (RNA polymerase is called a holoenzyme when sigma subunit is attached to the core enzyme which is consist of 2 α subunits, 1 β subunit, 1 β' subunit only). Unlike eukaryotes, the initiating nucleotide of nascent bacterial mRNA is not capped with a modified guanine nucleotide. The initiating nucleotide of bacterial transcripts bears a 5′ triphosphate (5′-PPP), which can be used for genome-wide mapping of transcription initiation sites. [35]

In archaea and eukaryotes, RNA polymerase contains subunits homologous to each of the five RNA polymerase subunits in bacteria and also contains additional subunits. In archaea and eukaryotes, the functions of the bacterial general transcription factor sigma are performed by multiple general transcription factors that work together. [7] In archaea, there are three general transcription factors: TBP, TFB, and TFE. In eukaryotes, in RNA polymerase II-dependent transcription, there are six general transcription factors: TFIIA, TFIIB (an ortholog of archaeal TFB), TFIID (a multisubunit factor in which the key subunit, TBP, is an ortholog of archaeal TBP), TFIIE (an ortholog of archaeal TFE), TFIIF, and TFIIH. The TFIID is the first component to bind to DNA due to binding of TBP, while TFIIH is the last component to be recruited. In archaea and eukaryotes, the RNA polymerase-promoter closed complex is usually referred to as the "preinitiation complex." [36]

Transcription initiation is regulated by additional proteins, known as activators and repressors, and, in some cases, associated coactivators or corepressors, which modulate formation and function of the transcription initiation complex. [7]

Promoter escape Edit

After the first bond is synthesized, the RNA polymerase must escape the promoter. During this time there is a tendency to release the RNA transcript and produce truncated transcripts. This is called abortive initiation, and is common for both eukaryotes and prokaryotes. [37] Abortive initiation continues to occur until an RNA product of a threshold length of approximately 10 nucleotides is synthesized, at which point promoter escape occurs and a transcription elongation complex is formed.

Mechanistically, promoter escape occurs through DNA scrunching, providing the energy needed to break interactions between RNA polymerase holoenzyme and the promoter. [38]

In bacteria, it was historically thought that the sigma factor is definitely released after promoter clearance occurs. This theory had been known as the obligate release model. However, later data showed that upon and following promoter clearance, the sigma factor is released according to a stochastic model known as the stochastic release model. [39]

In eukaryotes, at an RNA polymerase II-dependent promoter, upon promoter clearance, TFIIH phosphorylates serine 5 on the carboxy terminal domain of RNA polymerase II, leading to the recruitment of capping enzyme (CE). [40] [41] The exact mechanism of how CE induces promoter clearance in eukaryotes is not yet known.

Elongation Edit

One strand of the DNA, the template strand (or noncoding strand), is used as a template for RNA synthesis. As transcription proceeds, RNA polymerase traverses the template strand and uses base pairing complementarity with the DNA template to create an RNA copy (which elongates during the traversal). Although RNA polymerase traverses the template strand from 3' → 5', the coding (non-template) strand and newly formed RNA can also be used as reference points, so transcription can be described as occurring 5' → 3'. This produces an RNA molecule from 5' → 3', an exact copy of the coding strand (except that thymines are replaced with uracils, and the nucleotides are composed of a ribose (5-carbon) sugar where DNA has deoxyribose (one fewer oxygen atom) in its sugar-phosphate backbone). [ citation needed ]

mRNA transcription can involve multiple RNA polymerases on a single DNA template and multiple rounds of transcription (amplification of particular mRNA), so many mRNA molecules can be rapidly produced from a single copy of a gene. [ citation needed ] The characteristic elongation rates in prokaryotes and eukaryotes are about 10-100 nts/sec. [42] In eukaryotes, however, nucleosomes act as major barriers to transcribing polymerases during transcription elongation. [43] [44] In these organisms, the pausing induced by nucleosomes can be regulated by transcription elongation factors such as TFIIS. [44]

Elongation also involves a proofreading mechanism that can replace incorrectly incorporated bases. In eukaryotes, this may correspond with short pauses during transcription that allow appropriate RNA editing factors to bind. These pauses may be intrinsic to the RNA polymerase or due to chromatin structure. [ citation needed ]

Termination Edit

Bacteria use two different strategies for transcription termination – Rho-independent termination and Rho-dependent termination. In Rho-independent transcription termination, RNA transcription stops when the newly synthesized RNA molecule forms a G-C-rich hairpin loop followed by a run of Us. When the hairpin forms, the mechanical stress breaks the weak rU-dA bonds, now filling the DNA–RNA hybrid. This pulls the poly-U transcript out of the active site of the RNA polymerase, terminating transcription. In the "Rho-dependent" type of termination, a protein factor called "Rho" destabilizes the interaction between the template and the mRNA, thus releasing the newly synthesized mRNA from the elongation complex. [45]

Transcription termination in eukaryotes is less well understood than in bacteria, but involves cleavage of the new transcript followed by template-independent addition of adenines at its new 3' end, in a process called polyadenylation. [46]


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Eukaryotic Repressors

Gene expression in eukaryotic cells is regulated by repressors as well as by transcriptional activators. Like their prokaryotic counterparts, eukaryotic repressors bind to specific DNA sequences and inhibit transcription. In some cases, eukaryotic repressors simply interfere with the binding of other transcription factors to DNA (Figure 6.30A). For example, the binding of a repressor near the transcription start site can block the interaction of RNA polymerase or general transcription factors with the promoter, which is similar to the action of repressors in bacteria. Other repressors compete with activators for binding to specific regulatory sequences. Some such repressors contain the same DNA-binding domain as the activator but lack its activation domain. As a result, their binding to a promoter or enhancer blocks the binding of the activator, thereby inhibiting transcription.

Figure 6.30

Action of eukaryotic repressors. (A) Some repressors block the binding of activators to regulatory sequences. (B) Other repressors have active repression domains that inhibit transcription by interactions with general transcription factors.

In contrast to repressors that simply interfere with activator binding, many repressors (called active repressors) contain specific functional domains that inhibit transcription via protein-protein interactions (Figure 6.30B). The first such active repressor was described in 1990 during studies of a gene called Krüppel, which is involved in embryonic development in Drosophila. Molecular analysis of the Krüppel protein demonstrated that it contains a discrete repression domain, which is linked to a zinc finger DNA-binding domain. The Krüppel repression domain could be interchanged with distinct DNA-binding domains of other transcription factors. These hybrid molecules also repressed transcription, indicating that the Krüppel repression domain inhibits transcription via protein-protein interactions, irrespective of its site of binding to DNA.

Many active repressors have since been found to play key roles in the regulation of transcription in animal cells, in many cases serving as critical regulators of cell growth and differentiation. As with transcriptional activators, several distinct types of repression domains have been identified. For example, the repression domain of Krüppel is rich in alanine residues, whereas other repression domains are rich in proline or acidic residues. The functional targets of repressors are also diverse. Some repressors inhibit transcription by interacting with general transcription factors, such as TFIID others are thought to interact with specific activator proteins.

The regulation of transcription by repressors as well as by activators considerably extends the range of mechanisms that control the expression of eukaryotic genes. One important role of repressors may be to inhibit the expression of tissue-specific genes in inappropriate cell types. For example, as noted earlier, a repressor-binding site in the immunoglobulin enhancer is thought to contribute to its tissue-specific expression by suppressing transcription in nonlymphoid cell types. Other repressors play key roles in the control of cell proliferation and differentiation in response to hormones and growth factors (see Chapters 13 and 14).


The interplay of miRNAs and TFs in autophagy regulation in NAFLD

miRNAs and TFs often play coordinating roles in the regulation of various cellular processes via a complex signal transduction network in the liver 134,135 . For example, in human HCC cells, miR-223 and FOXO3a modulate doxorubicin-induced cytoprotective autophagy, contributing to chemoresistance. However, miR-223 overexpression suppresses Foxo3a-modulated autophagy, which enhances doxorubicin sensitivity in a mouse xenograft model of HCC, suggesting that this miRNA/TF axis is an important mechanism for drug resistance development in HCC 136,137 . TFEB-mediated transactivation is also regulated by miR-30-5p, which suppresses TFEB-dependent downstream gene expression by binding to coordinated lysosomal expression and regulation element, leading to the inhibition of lysosomal biogenesis and autophagy in mouse liver 138 .

Accumulating evidence shows that miR-34a is involved in NAFLD, and miR-34a expression is increased in NASH patients and in obese or diabetic mice 108,139,140 . miR-34a promotes hepatic steatosis through the suppression of various TFs, such as HNF4α 141 , PPARα, and SIRT1, which promote the expression of autophagy-related genes 142,143,144 . These observations suggest that the miR-34a/TF axis may inhibit NAFLD progression through transcriptional regulation of autophagy 52,109,130,145 . Interestingly, miR-34a is directly activated by nuclear receptor liver X receptor-α, a ligand-dependent TFr involved in hepatic cholesterol metabolism. miR-34a also inhibits Atg4B and Rab8b, which regulate autophagic flux, leading to the progression of hepatic steatosis 146,147 . Considering the role of LXR in cholesterol homeostasis and that increased hepatic free cholesterol is associated with the development of NASH from NAFL in obese mice, cross-talk between TFs, miR-34a, and autophagy may be important for controlling NASH development.

Recently, we reported certain miRNAs and TFs that regulate autophagy in the development of HFD-induced fatty liver. As shown in Fig. 5, we found that miR-214-3p and HNF4α modulated Ulk1 expression and autophagy in hepatocytes 52 . Our results indicate that autophagy in the fatty liver was attenuated only when mice were fed a 45% HFD for a prolonged period, which led to a significant reduction in the expression of autophagy-related genes, such as Ulk1. This downregulation of autophagy was caused by increased miR-214-3p and decreased HNF4α levels in hepatocytes. miR-214-3p negatively regulates Ulk1 expression through direct binding of the 3´-UTR sequence of Ulk1, and HNF4α induces autophagy by directly binding Ulk1, promoting its transcription. Thus, both miR-214-3p and HNF4α act as regulatory factors of Ulk1 expression. Although the inhibition of miR-214-3p in the fatty liver appears to restore HNF4α expression, miR-214-3p does not directly regulate HNF4α, suggesting that miR-214-3p and HNF4α independently regulate Ulk1 expression. The interplay between miR-214-3p and HNF4α and their involvement in the regulation of autophagy in the fatty liver are summarized in Fig. 5. Taken together, we propose that miR-214-3p and HNF4α are potential targets for NAFLD therapy.

miR-30b-5p and miR-34a downregulate autophagy-related gene expression by directly inhibiting TFs, such as transcription factor EB (TFEB), Hnf4α, peroxisome proliferator-activated receptor alpha (PPARα), and NAD-dependent protein deacetylase sirtuin 1 (SIRT1). Liver X receptor-α (LXRα) transcriptionally activates miR-34a and let7a, which directly target the 3’UTR of Atg4B and Rab8b. miR-214-3p and HNF4α reciprocally regulate Ulk1 expression.


Overview of the Stages of Transcription

The basic steps of transcription are initiation, elongation, and termination. Here we can identify several of the DNA sequences that characterize a gene. The promoter is the binding site for RNA polymerase. It usually lies 5&rsquo to, or upstream of the transcription start site. Binding of the RNA polymerase positions the enzyme to near the transcription start site, where it will start unwinding the double helix and begin synthesizing new RNA. The transcribed grey DNA region in each of the three panels are the transcription unit of the gene. Termination sites are typically 3&rsquo to, or downstream from the transcribed region of the gene. By convention, upstream refers to DNA 5&rsquo to a given reference point on the DNA (e.g., the transcription start-site of a gene). Downstream then, refers to DNA 3&rsquo to a given reference point on the DNA.

Figure (PageIndex<2>): Three steps of transcription. (Copyright )


For more information about gene regulation:

The National Human Genome Research Institute provides a definition of gene regulation in their Talking Glossary of Genetic Terms.

The Genetic Science Learning Center at the University of Utah offers an explanation of gene expression as it relates to disease risk.

Additional information about gene expression is available from yourgenome.org, a service of the Wellcome Trust.

The Khan Academy has an educational unit on gene regulation, including videos about gene regulation in bacteria and eukaryotes.


Watch the video: eukaryotische Genregulation (January 2023).