Gene Expression

Mechanisms of Transcription Regulation

Transcription is regulated by regulatory DNA sequences, which interact with activators, repressors, and enhancers to increase or decrease the amount of mRNA made.

It is vital that a cell carries out processes at the appropriate times but not at others. Therefore, cells have mechanisms of regulation of transcription and translation so that only the proteins needed are produced at any time, depending on environmental factors.

The cell can control the amount of a protein produced by controlling when a gene is transcribed, controlling the splicing of the RNA transcribed from a gene, selectively allowing transport of some RNA, but not others from the nucleus to the cytoplasm, selectively translating some mRNAs but not others, and controlling how quickly mRNA is degraded after translation occurs. Additionally, cells might use regulatory mechanisms related directly to proteins, such as selectively degrading some proteins quickly.

Because control of gene transcription minimizes wasted steps (and thus wasted energy), it is the most common regulatory mechanism. A transcriptional switch turns transcription on or off, allowing the correct amount of mRNA to be transcribed. Such switches often take the form of a regulatory DNA sequence, which is a nucleotide sequence that can increase or decrease gene expression. A regulatory DNA sequence does not operate by itself; rather, it works through the action of a transcription factor, a protein that binds to the regulatory DNA sequence to control transcription. The proteins involved in regulation of transcription can be repressors or activators. A repressor is a protein that inhibits transcription of a gene. An activator is a protein that increases transcription of a gene.

The simplest examples of regulation of transcription occur in bacteria. Many bacteria have operons. An operon is a collection of genes that are transcribed together and contain at least two regions of control called a promoter and an operator. Bacteria may have many operons, but operons are rarely found in eukaryotes. Among the most well-studied bacterial operons are the trp operon and the lac operon, belonging to E. coli.

Trp Operon

Found in E. coli bacteria, the trp operon is a group of genes that function together to regulate the production of tryptophan.
The trp operon is a gene cluster that codes for the production of the amino acid tryptophan. When tryptophan is absent, RNA polymerase (which builds mRNA) binds to the promoter region of DNA preceding the tryptophan genes and transcription proceeds as normal. As tryptophan is produced and builds up in the surrounding area, it binds to a repressor protein. The repressor-protein molecule then binds to the operator region, preventing binding by RNA polymerase and therefore preventing transcription. This prevents the unnecessary transcription of tryptophan-producing proteins when tryptophan levels are already sufficient. The trp operon is also regulated by a process called attenuation. The attenuator region controls transcription after RNA polymerase initiates synthesis. The level of tryptophan available in the cell determines the position of the ribosomes and the rate at which they are translating. Abundant tryptophan favors a ribosome conformation that ultimately leads to termination of transcription.

Lac Operon

Found in E. coli bacteria, the lac operon is a group of genes that function together to regulate the transport and metabolism of lactose.

The lac operon is a gene cluster that codes for enzymes that import and digest the sugar lactose in E. coli and other bacteria. Normally, an E. coli cell gets its energy from glucose. However, glucose is not always available in the environment. Sometimes, lactose is present at higher amounts. Under these conditions, the lac operon allows the cell to switch from using glucose for energy to using lactose. This operon is under the control of both an activator and a repressor, which means it requires both the absence of glucose and the presence of lactose for full expression. These requirements prevent the production of enzymes that are not usable because of current environmental conditions.

In the absence of glucose, the activator protein CAP increases gene expression of the lactose genes by helping RNA polymerase bind to the promoter. One such gene that is expressed is the LacZ gene, whose protein product ultimately cleaves the disaccharide lactose into glucose and galactose. CAP must bind cyclic AMP (cAMP) before it can bind to the DNA at a region called the CAP binding site, which sits just before the promoter. This is only possible when cAMP levels are high. As cAMP levels only rise in lower concentrations of glucose, CAP can only bind to DNA once glucose is absent or in very low concentrations.

However, in the absence of lactose, the lac repressor protein binds to the operator, a sequence within the promoter. This prevents RNA polymerase from binding to the promoter and initiating transcription. If lactose is present, however, the lac repressor protein releases the operator, and RNA polymerase can bind and transcribe the genes for lactases, the enzymes that digest lactose.
The lac operon is a cluster of genes that codes for lactose transport and digestion proteins in E. coli. In the absence of glucose, cyclic AMP (cAMP) binds to the CAP activator to begin transcription. When lactose is absent, the lac repressor binds to the operator and blocks RNA polymerase from binding, preventing transcription.
Operons exist primarily in prokaryotes, but they do occur in some eukaryotes, namely the Drosophila melanogaster fruit fly and Caenorhabditis elegans nematode. For all other eukaryotes, gene regulation takes the form of repressors, which halt transcription of a gene, and activators, which promote gene transcription. By turning specific genes on or off at different times during the development of the organism, a single-celled zygote transforms into a mature multicellular organism with varied cell and tissue types that perform diverse and specialized functions. Early embryos have stem cells that have the potential to become any cell type. A pluripotent stem cell is a cell able to reproduce indefinitely and develop into other types of specialized cells. These cells give rise to all body cell types by activating the right genes at the right times. Through a combination of activators and repressors, these cells become bone, skin, or muscle cells, along with all the other cells of the body. Eukaryotes often have an enhancer to increase transcription of a gene. An enhancer is a region of DNA that encourages transcription by binding proteins that help initiate it. The enhancer can increase the likelihood that transcription will occur by binding proteins that help initiate transcription. The three-dimensional structure of the DNA molecule often affects the efficacy of the enhancer. Enhancer elements can thus be located far away on the DNA strand in relation to the promoter, even thousands of bases away.

Enhancer Region of DNA

In eukaryotes, an enhancer is a DNA sequence that increases gene expression, which may lie far away on a DNA strand from the gene it controls. Enhancers require the help of transcription factors, enzymes that help bind RNA polymerase to the promoter.