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= Transcriptional Repression = Transcriptional repression is a type of transcriptional regulation that works to dampen gene expression. It is carried out by molecules generally known as repressors, although some have activating and repressing abilities depending on the circumstance, such as with allosteric repression. An example is the tryptophan inducible repression of tryptophan synthesis in E. coli. In prokaryotes, transcriptional regulation is the primary controller of gene expression, as most genes are active by default. Eukaryotic genes, by contrast, spend most of their time repressed or completely silenced. Additionally, eukaryotes impose regulation on all stages of gene expression, including but not limited to transcription. Nevertheless, transcriptional repression plays a significant role in all cell types. Its most common roles are to increase metabolic efficiency based on available energy resources (particularly for prokaryotes) and to regulate the growth and differentiation of cells (particularly for eukaryotes).

Transcriptional repressors can interact directly or indirectly with the DNA. They can bind to DNA elements or interact with transcription factor and activator proteins. Thus, repression range from general to specific, depending on whether repressors interact with specific DNA elements and gene-specific molecules or with general transcription factors and transcriptional machinery.

Methods of Transcriptional Repression
Three major places for repressors to interfere with transcription are by inhibiting RNA polymerase (RNAP) binding, inhibiting the transition of closed to open transcription complex, and preventing RNAP from detaching from the promoter to begin making the RNA transcript. General strategies of prokaryotes will be discussed to cover basic concepts, since eukaryotes use a greater breadth and depth of methods.

Sigma Factors
Bacterial RNAP needs to combine with a sigma subunit to begin transcribing. There are multiple classes of sigma subunits that enable transcription of different subsets of genes. Since their effects on RNAP are concentration-dependent, different sigma subunits can compete with each other or anti-sigma factors can sequester sigma factors, changing gene expression.

Promoter Recognition Interference
Repressors, including those originating from bacteriophages, can bind to promoter recognition sites, preventing RNAP from binding and transcribing. Sometimes, one class of RNAP can act as an inhibitor against another class of RNAP that is necessary for transcription of a particular gene.

Distant Repressor Nucleation
Cis regulatory elements up to a few hundred base pairs from the transcription start site (not to be confused with distal control elements) can serve as binding sites for a repressor molecule. In turn, other repressor molecules can build on top of the initial one, ultimately blocking RNAP's access to the promoter, even though they do not bind to the promoter itself.

Promoter Melting Inhibition
Repressors are known to interfere with promoter melting, which is the localized denaturation of nucleotides that mark the beginning of an open transcription complex.

Certain repressors can prevent the DNA from bending in necessary ways to transition from a closed to open complex. It is possible for RNAP and a repressor to simultaneously bind to opposite strands of DNA, either at the same or different sites, preventing the DNA from opening up a transcription bubble. Also, some repressors bind to the DNA in ways that prevent distal control elements and the promoter from making contact and forming an open transcription complex.

Promoter Clearance Inhibition
Promoter clearance is the separation of RNAP from the initiation complex into the transcribed gene sequence. There is a careful balance between the opposing forces of promoter binding specificity and promoter clearance. In prokaryotes, p4 protein and adenine/thymine series upstream from the promoter are known for repressing highly stabilized transcription complexes. They do so by holding onto the carboxy-terminal domain of RNAP’s alpha subunit, preventing it from clearing the complex. Additionally, some proteins function by altering the shape of open complexes (rather than inhibiting them from forming, as was previously discussed). However, such shape changes can prevent efficient RNAP clearance. Finally, repressors are able to act as nearby downstream roadblocks that prevent RNAP from progressing just after clearing the initiation complex. The significance of these downstream repressors decreases further downstream because RNAP has already had sufficient distance to form a stable elongation complex.

General
Some repressors are able to widely repress transcription by inhibiting or altering general transcription machinery or modifying chromatin structure.

General Transcription Factor Repression
Some repressors bind to widely used general transcription factors (TFs) and prevent them from functioning. For example, Dr1 binds to a general TF known as TATA binding protein (TBP, or TFIID) and prevents it from binding to another transcription factor, TFIIB. It is also able to indirectly interfere with another general TF, TFIIA, by binding to it or changing the conformation of DNA at TFIIA binding sites. NOT proteins are also an example of a repressor that targets TBP among other general transcriptional components.

Another repressor known as Mot1 competes with TFIIA for TBP binding. Mot1 removes TBP from its DNA binding site while TFIIA stabilizes it. The three components act in a concentration dependent manner, with low levels of Mot1 actually being helpful in recruiting TBP away from nonfunctional promoters. Thus, Mot1 only has repressive behaviors under certain conditions, which happens to be true for many repressors.

Additionally, there are repressors that interact with general transcription factors and their coactivators, causing repression; one such example in eukaryotes is RBP.

RNA Polymerase Interference
Further building on interference with common transcriptional machinery, RNA polymerase is also a target of some repressors. In yeast (eukaryotes), Srb10 kinase phosphorylates the carboxy-terminal repeat domain of an RNAP II subunit, preventing RNAP II from joining a transcription complex.

General Chromatin Modification
It is possible for repressors to indirectly lead to chromatin altering by interfering with histone modifiers. Activities that enhance histone deacetylases and histone methyltransferases or inhibit histone acetyltransferases and histone demethylases reduce the expression of target genes. For example, Rb tumor suppressor protein binds with SMRT proteins (silencing mediator of retinoid and thyroid hormone receptors) and Sin3, a histone deacetylase complex, leading to local chromatin alteration.

Gene-Specific
Coregulator molecules, which include coactivators and corepressors, interact with general transcription factors. Oftentimes, they can activate some genes and repress others. Coregulators can directly bind to transcription factors and other pieces of basal transcription machinery (assembling and activating transcription complexes), interact with other coregulators, and alter chromatin structure (as is the case with histone methyltransferases, histone acetyltransferases, and ATP-dependent remodeling complexes).

It has been established that coregulator molecules tend to be gene-specific, allowing for a smaller set of general transcription factors to regulate many genes with the help of specific coregulators. For example, RBP is known to interfere with coactivators TAFII110 and TFIIA, which in turn prevents TAFII110 from effectively interacting with activator Sp1.