23Gene Regulation in Eukaryotes

23Gene Regulation in Eukaryotes - Gene Regulation in...

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Unformatted text preview: Gene Regulation in Eukaryotes Introduction The molecular mechanisms that underlie gene regulation in eukaryotes bear many similarities to the ways that bacteria regulate their genes. As in prokaryotes, regulation in eukaryotes can occur at any step in the pathway of gene expression (Figure 15.1). Regulatory Transcription Factors General information Proteins that influence the ability of the RNA polymerase to transcribe a gene are called transcription factors. General transcription factors bind the RNA polymerase to the core promoter. Regulatory transcription factors regulate the rate of gene transcription. These proteins typically recognize cis regulatory elements that are similar to operators in bacteria. These regions are generally known as control elements or regulatory elements. Transcription factors that increase the rate of transcription are called activators, and the regulatory element DNA sequence they bind to is called an enhancer (Figure 15.2a). Transcription factors that decrease the rate of transcription are called repressors, and the DNA sequence they bind to is called a silencer (Figure 15.2b). Most eukaryotic genes, particularly those found in multicellular species, are regulated by many factors; this phenomenon is called combinational control. At the level of transcription, the following are common factors that contribute to combinational control: One or more activator proteins may stimulate the ability of RNA polymerase to initiate transcription. One or more repressor proteins may inhibit the ability of RNA polymerase to initiate transcription. The function of activators and repressors may be modulated in a variety of ways; these include the binding of small effector molecules, protein-protein interactions, and covalent modifications. 1 c is enhancer silencer DNA? DNA meth compacts DNA and turns it off Activator proteins may promote the loosening of chromatin compaction in the chromosome where the gene is located, thereby making it easier for the gene to be recognized and transcribed by RNA polymerase. DNA methylation may inhibit transcription, either by preventing the binding of an activator protein or by recruiting proteins that cause the chromatin to become more compact. All five of these factors can contribute to the regulation of a single gene, or possibly only three or four will play a role. In most cases, transcriptional regulation is aimed at controlling the initiation of transcription at the promoter. Structural features of regulatory transcription factors allow them to bind to DNA. There are different families of evolutionarily related transcription factors. how does it actually bind t o DNA? Molecular structure of transcription factor proteins that allows them to bind to DNA is an area of intense research. Domains are regions of transcription factors that have specific functions. as in tryptophan to trp and allolactose to lac repressor For example, one domain may have a DNA-binding function, while another may provide a binding site for a small effector molecule. A domain that has a similar structure in many different proteins is called a motif. The different types of protein motifs are illustrated in Figure 15.3. The protein secondary structure known as an ! helix is frequently found in transcription factors. The ! helix is the proper width to bind into the major groove of the DNA double helix. can be a homodimer or a heterodimer - two slightly different molecules Certain motifs (e.g., helix-loop-helix and leucine zipper) promote protein dimerization. Two identical transcription factors that come together are called a homodimer. Two different transcription factors that interact are called a heterodimer. helix turn helix - 2 Regulatory transcription factors recognize regulatory elements that function as enhancers or silencers. Regulatory elements that up regulate transcription are called enhancers. Typically they increase activity 10- to 1,000-fold. Regulatory elements that down regulate transcription are called silencers. one is just the other upside down activator or repressor can attach in either orientation Many regulatory elements are orientation independent, or bidirectional; i.e., the regulatory element can function in the forward or reverse direction. For example, the regulatory transcription factor will bind to an enhancer oriented: Forward 5’–GATA–3’ 3’–CTAT–5’ or Reverse 5’–TATC–3’ 3’–ATAG–5’ TFIID - whether it is going to bind at all to t he promotor, or activated or repressed at the promoter if it is already attached ...that's what is impt once it has been assembeld (all parts) is it going to go or not go?...next impt point with activator protein t rans activator attaches to enhancer mediator, GTF comes off and the thing goes repressor protein....regulatory t ranscritpion factor attaches to silencer and turns it off and it just doesn't go Most regulatory elements are located within a few hundred base pairs upstream from the promoter site, but the distance can be thousands of base pairs away. Regulatory transcription factors may exert their effects through TFIID and mediator Most regulatory transcription factors do not bind directly to the RNA polymerase. Instead, they interact with either TFIID or mediator (Figure 15.4). Some regulatory transcription factors exert their effects through TFIID, a general transcription factor that binds to the TATA box and recruits RNA polymerase to the core promoter (Figure 15.4a). Transcriptional activators may recruit TFIID to the core promoter and/or activate its function, while repressors inhibit TFIID binding or its activity. Some regulatory transcription factors exert their effects through mediator, which plays a pivotal role in the switch between transcriptional initiation and elongation (Figure 15.4b). By interacting with mediator in different ways, activators stimulate transcription, while repressors inhibit transcription. The function of regulatory transcription factor proteins can be modulated in three ways. Regulatory transcription factors must be regulated for the same reason as genes. There are three basic mechanisms of regulating transcription factor function (Figure 15.5). The binding of an effector molecule (Figure 15.5a). An example is steroid hormomes. protein protein interaction ---two trans factors bind to another to make a homodimer regulatory t ranscritption binding of small effector molecule s uch as a hormone attaches to trans covalent modifi cation such as phosphorylation...inactive if not phosphorylated and active if it is.... 3 Protein-protein interactions (Figure 15.5b). An example is the formation of homodimers and heterodimers. Covalent modification of the transcription factor (Figure 15.5c). An example is the addition of a phosphate group. glucocorticoid is going toa t tach to receptor and proteins attached to receptor are going to be relased from it... NLS are available Steroid hormones exert their effects by binding to regulatory transcription factors. Regulatory transcription factors that interact with steroid hormones are called steroid receptors. Steroid hormones are designed to influence gene expression. Steroid hormones are synthesized by endocrine glands (mammals). The action of a glucocorticoid receptor is illustrated in Figure 15.6. Binding of the hormone to the glucocorticoid receptor releases a protein called HSP90, exposing a nuclear localization signal (NLS). Two glucocoricoid receptors form a dimer and bind to glucocorticoid response elements (GREs) in the nucleus. This activates the transcription of adjacent target genes. glucocort binds to different s ite on the receptor two receptors form a dimer and bind to GRE's and this activates transcription gluccocort is an effector t hat is an inducer gluco receptor is a dimer t hat is a trans element The CREB protein is an example of a regulatory transcription factor modulated by covalent modification. Most signaling molecules bind to receptors on the plasma membrane. This generates an intracellular signal, causing a cellular response. One of these responses may be transcription. The cAMP response-element binding protein (CREB) is an example (Figure 15.7). CREB proteins are regulatory transcription factors that become activated in response to cyclic-adenosine monophosphate (cAMP). The response element is called a cAMP response element (CRE). gluco response elemtnts are an enhancer Changes in Chromatin Structure General information Alterations in DNA structure can affect gene expression by a variety of mechanisms (Table 15.1). Chromatin compaction. Tightly packed chromatin is said to be in the closed configuration. Chromatin in the open configuration is more accessible to transcription factors and RNA polymerase. 4 ...
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