4.2Regulation of Genes by Feedback


Gene Regulatory Mechanisms Coded in the Genome

Gene activity is complex because many genes in living organisms are not always expressed in the same manner, but are expressed differently in response to changes in the external environment. In the 1950s, François Jacob and Jacques Monod demonstrated with experiments on Escherichia coli that the regulation of expression of genes that transcribe RNA from DNA is the key to maintaining the internal environment within a certain range (see Column below [4.2.2]).
In E. coli, glucose is made by breaking down lactose—another sugar. This reaction is controlled by β-galactosidase enzyme. When the amount of glucose decreases, the mRNA that produces β-galactosidase increases; consequently, β-galactosidase is produced, and the glucose concentration increases. However, when the amount of lactose decreases, the mRNA that produces β-galactosidase decreases, and β-galactosidase thus decreases. Consequently, lactose does not get broken down, and its concentration increases (Fig. 4-3).
The mechanism that senses these changes in environmental factors and maintains the sugar concentrations at a constant level is referred to as "feedback regulation." In the above example, a rising lactose concentration increases mRNA, a lactose-degrading enzyme, and lactose thus decreases. Conversely, a descending lactose concentration decreases mRNA, and the lactose thus increases. This process is referred to as "negative feedback regulation" because its output is in the opposite direction of its input. Negative feedback regulation is a mechanism that maintains constant internal environment in a manner similar to how a thermostat of an air conditioner maintains the temperature of a room by heating it when the temperature drops and cooling it when the temperature rises.

Fig. 4-3. Regulation of Sugar Metabolism in E. coli

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Various Types of Feedback Regulation

Feedback is controlled by various proteins. As shown in Figure 4-4, for feedback regulation, first there must be a protein that senses conditions. In the above example of lactose in E. coli, the sensor is a repressor that senses the concentration of lactose. Thus, when this repressor senses the lactose concentration, it regulates the expression of the gene, makes functional proteins such as enzymes that break down the lactose, and acts to maintain homeostasis. In this case, the regulation of sugar content is negative feedback, which decreases an augmented component and increases an insufficient component.
Conversely, there is also a mechanism called "positive feedback," which outputs in the same direction as the input, for example, by promoting synthesis of a substance when its concentration has increased. During positive feedback, a reaction continues once it has started. However, if the reaction cannot stop and begins a vicious cycle, the positive feedback cannot sustain inside the cell, which has limited resources.
This kind of positive feedback is often used by cells when they differentiate into specialized cells. Below is an example of the differentiation of blood cells.

The differentiation of red blood cells depends on a gene called GATA1*1. Proteins that regulate the expression of genes by binding to DNA are referred to as "transcription factors." The GATA1 protein is a transcription factor. It binds to the GATA sequence in the regulatory sequence of DNA, but is actually known to bind to the regulatory sequence of the GATA1 gene itself.
In cells that are precursors of red blood cells, activated GATA1 protein binds to a regulatory sequence of the GATA1 gene itself in DNA and promotes expression of the GATA1 gene. Once this happens, positive feedback occurs, in which the activation of the GATA1 protein stimulates expression of the GATA1 protein itself. The GATA1 protein is continuously produced, thus promoting differentiation into red blood cells. As differentiation proceeds, the nucleus containing genes is expelled from each cell, making cell proliferation impossible. Ultimately, differentiated red blood cells specialize in carrying enzymes.
In the human body, feedback is carried out by not one cell but by multiple cells. For example, blood sugar is regulated by negative feedback (Fig. 4-4B). The amount of sugar in the blood is sensed by β cells of the pancreas. β cells secrete a hormone called "insulin" into the blood. Muscle and fat cells contain insulin receptors, and if these receptors sense an increase in the concentration of insulin in the blood, the sugar in the blood is absorbed into the cells. At the same time, insulin inhibits sugar synthesis in the liver. Thus, various cells cooperate to lower the blood sugar level and maintain homeostasis (see Chapter 8, Fig. 8-6).

*1 Normally, names of genes are written in Italics.

Fig. 4-4. Intracellular and Intercellular Feedback Regulatory Mechanisms


Discovery of the Mechanisms of Gene Regulation by Jacob and Monod

Our genes have two types of sequence: one that contains information about protein structure, and the other that regulates the expression of that information, i.e., the transcription of RNA from DNA. Column Figure 4-1A shows the sequence involved in regulation of the gene for β-galactosidase, which breaks down lactose and produces glucose. The sequence involved in this regulation lies upstream of another sequence that contains information about protein structure. First, there is a sequence that binds with an activator protein that activates RNA synthesis. This activator protein binds to the sequence GTGAGXXXXCTCAC (X is any base) made of the four bases A, G, C, and T.
Next, another sequence binds with RNA polymerase, which synthesizes RNA. When the activator and RNA polymerase bind to the DNA, RNA is produced to make enzyme proteins.
Then, a sequence binds with a protein that represses RNA synthesis. If a repressor protein binds to this sequence, RNA polymerase cannot produce RNA.
As shown in Column Figures 4-1B and C, when the concentration of lactose is high, lactose metabolic products bind to the repressor and prevent it from binding to DNA. If the concentration of a chemical called cyclic AMP (cAMP) increases in the cell at that time, the activator binds to DNA. Once that happens, β-galactosidase is produced, lactose gets broken down, and the glucose level increases.
When the glucose level increases, the concentration of cyclic AMP decreases, thus preventing the activator from binding DNA. At the same time, decreases in lactose concentration enable the repressor to bind to DNA, thereby preventing production of RNA for the enzyme.
In this manner, proteins sense changes in environmental factors, alter their structures, and regulate genes. An enzyme gene that converts lactose to glucose monitors the concentration of cAMP, and the breakdown of lactose into glucose proceeds only when there is a large amount of lactose and a small amount of glucose. Such regulation is often accurately and precisely performed by multiple regulation systems to maintain the environment inside the bodies of living organisms.

Column Fig. 4-1. Feedback Regulation of Gene Expression by Activators and Repressors

(A) Structure of the β-galactosidase gene
(B) In E. coli, when there is a small amount of lactose, a repressor binds to the regulatory sequence of the gene and represses RNA expression.
(C) When there is a large amount of cAMP, it stimulates the activators, which synthesize RNA.

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Feedback Regulation that Generates Biological Rhythms

Fig. 4-5. Vibration to be created through feedback control

The activities of many organisms have rhythms. Various rhythmic changes of varying durations are known. For example, heartbeat repeats in a cycle as short as about 1 second. Behaviors such as eating and sleeping, namely "circadian rhythms," occur every 24 hours. Menstrual cycle in women repeats in about every 30 days. Most animals undergo hibernation once a year. For such activities, when the feedback of the systems that activate genes and of those that repress them work together simultaneously, rhythmic oscillation occurs.
An example of a mechanism for oscillatory regulation is shown in Figure 4-5. Many repetitious structures, such as the spine, exist in the bodies of animals. To make such repetitious structures, Hes gene shown in Figure 4-5A is expressed every 1 to 2 hours. Hes protein binds to a sequence that regulates its own Hes gene and represses its expression. This feedback regulation, in which a protein represses the expression of the very gene that produces it, generates a biological rhythm based on two conditions.
First, there must be stimulation constantly activating the Hes gene. Second, the protein produced by the Hes gene must break down at a suitable rate. When these conditions are satisfied, an increased concentration of the Hes protein represses expression of the Hes gene, thus decreasing the concentration of the RNA that it transcribes. Next, when the protein breaks down, the expression of the I gene increases, thus increasing the concentration of its RNA. The RNA and protein shown in Figure 4-5B are expressed alternately in cycles. During the development of Drosophila flies, Hes RNA is expressed every 1–2 hours and repeatedly produces the same structure.
The 24-hour circadian rhythm is also based on the mechanism that induces gene expression every 24 hours. This oscillatory gene expression controls the cyclic behavior, which is referred to as "biological clock."


Chemicals that Can Be Both Poison and Medicine

More than a thousand of the 25,000 human genes code receptors (sensors) for various chemical substances. These receptors sense extremely low concentrations of chemical substances and activate the expression of genes.
If soil, water, or air contains even trace amounts of a chemical that acts on these receptors, the chemical may greatly affect the body by changing gene expression. Chemicals that accumulate in the bodies of organisms are also very dangerous if their concentrations exceed their natural levels. In particular, such chemicals have a major effect on fetuses during their development in pregnant women.
Knowledge of what kinds of chemicals are dangerous for the human body began to develop during the mapping of the human genome. Chemicals such as endocrine disrupters, which act on receptors in humans, are very hazardous even in trace amounts.
Chemicals are not always bad. Until today, various drugs with unknown mechanisms inside have been found to bind to these receptors and act on them. These include drugs for cancer, hypertension, and mental disorders. In genomic analysis, groups of genes containing information for similar proteins are called "families." The human genome includes the G protein-coupled receptor gene family, which contains over 800 genes that sense changes outside the cell. These families include histamine receptors that are targets of drugs for gastric ulcers, and also include angiotensin receptors that are targets of drugs for high blood pressure.
Other families include zinc-containing zinc finger-protein families. The proteins of these families are activators and repressors that bind to DNA and regulate gene expression. These families are the targets of adrenal cortex steroid hormone drug formulations, and female and male hormones.
Thus far, about half the drugs used for medical treatment have consisted of drugs that act on receptors such as G protein-coupled receptors and drugs that act on gene regulatory proteins such as zinc-finger proteins. Research has begun worldwide on millions of chemicals in order to discover many remaining candidates for drugs that target proteins of these families. This research is referred to as "Genome-based Drug Discovery."
Substances that act on proteins of receptors such as these G protein-coupled receptors and on gene regulatory proteins such as the zinc finger affect regulation systems in the human body. Consequently, such substances can be unsafe environmental chemicals, but they can also be drugs for various diseases.
In addition to the separation and duplication of genes, the genomes of living organisms are modified and altered from the time of birth. These modifications are referred to as the "epigenome." In what manner are these processes involved in the regulation of genes?

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