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How do hormones control genes? What do they have to do with the genome?



Why do I write about this topic?


I am writing about this topic because I was surprised by two findings at different times. First, at a neuroscience congress held annually in the U.S., I was walking through the poster session and stopped in front of a poster that showed the distribution of the estrogen receptor in the rat brain. This receptor binds the sex hormone estrogen. The rat is a mammal, and most of the molecular processes are similar to those in humans. The receptor appeared in nerve cells in almost all brain regions. Why does estrogen, known to regulate fertility in women, act in the brain, and why in so many places? Then, years later, a study was published showing that the estrogen receptor binds to more than 20,000 sites in the genome and thus influences the regulation of many genes. ‘Regulation’ relates to RNA transcription - a gene is turned on or off, and ‚fewer‘ or 'more' transcripts (RNA) are produced (I show an illustration further below).

So, let's get to the facts and start with the basics.


Terms:

1. Genome: refers to the information encoded in all DNA in a cell nucleus. In humans, all DNA is distributed among 23 chromosomes.

2. Transcription: the process of transcribing genes into RNA. Why RNA? RNA can travel out of the nucleus into the cytoplasm. It serves as a template for protein synthesis. This process is described and illustrated in my Blog article "Cell and gene therapy explained".




The basics: Two types of hormones - Why 'receptor'?


First, a hormone alone does nothing; it works with a partner to which it binds. The so-called binding partner is a receptor only suitable for this hormone. The property of hormones is that they are secreted by endocrine glands, which are controlled by the brain and then distributed throughout the body via the blood. When they meet their partner, they activate it to trigger a function. So there are two classes of hormones and, therefore, two classes of receptors. Let's call it System 1 and System 2.



Hormones bind to their receptors at the cell surface


System 1 uses larger molecules. The hormones cannot enter the cell but bind to their receptor, anchored on the cell surface. When this happens, the receptor undergoes a slight change in shape that signals the inside of the cell to implement a particular function. The transmission process from the signal outside into the cell is called signal transduction. Inside the cell, the signal is transmitted via shape changes and activations of several proteins, and this process is called a signal cascade.


Steroid hormones bind to their receptor in the cell nucleus


System 2 uses tiny molecules. These hormones, called steroid hormones, are also produced by endocrine glands and released into the blood. They pass through the membrane of cells and find their binding partners, the steroid receptors, in the cell plasma or even in the cell nucleus. Binding activates the steroid receptor to bind to the DNA at designated sites.



How do steroid hormones influence the gene activity?


So all steroid receptors are DNA-binding proteins called transcription factors. Steroid receptors belong to the large family of nuclear receptors; they are all transcription factors, i.e., regulatory proteins that activate or decrease the transcription of genes by binding to DNA.


Below I show a schematic of genomic DNA with two genes activated through transcription factors binding to their compatible enhancers. Subsequently, RNA can be synthesized.



The effect of steroid hormones


Most steroid hormones can be classified into five major classes: Progestogens, estrogens, androgens, glucocorticoids, and mineralocorticoids, which are grouped as corticosteroids.

You have probably recognized progestins and estrogens, the female sex hormones used in the contraceptive pill. The sex hormones, which include the androgens, on the one hand, produce the female and male sex in the development of the embryo and, on the other hand, regulate fertility and physical appearance in adulthood. However, as I pointed out in my introduction, these steroids also control other processes. Most of their production occurs in the gonads (ovaries, testes), but when these decrease their function in old age and cease in women, they are produced only in the adrenal cortex.



Steroid hormones control the stress response of the brain


Corticosteroids (glucocorticoids and mineralocorticoids) are produced in the adrenal cortex, and in general, they regulate metabolic processes. Let’s look at the stress response that is produced throughout the body as an answer to external stimuli, which the brain evaluates as dangerous and critical for taking action. Then the hypophysis releases a signal molecule into the bloodstream that induces the adrenal cortex to secrete the stress hormone cortisol. Cortisol is a glucocorticoid; it mediates 'stress' to the body but also ensures essential organ functions by stimulating basal metabolic rate. Cortisol levels in the blood are naturally highest in the early morning hours when the body is primed for activity. In a situation judged dangerous by the brain, cortisol is released, activating various organs to increase their metabolism to enable escape or appropriate physical response.



Steroid hormones switch genes 'on' and 'off'


Because steroid receptors are DNA-binding transcription factors, they can have higher-level effects. It just depends on the gene’s function that is activated or inhibited by a steroid receptor. Suppose it is a gene that codes for a protein controlling the activity of other genes. In that case, one can imagine a snowball effect in which individual steroids activate wide-ranging processes. Two examples are: (1) suppressing the 'inflammatory response' program or (2) activating the 'cell survival' program, preventing neuronal degeneration. Indeed, steroid hormones cross the blood-brain barrier. In the brain, progestogens and estrogen have anti-inflammatory effects and, thus, provide protection to nerve cells. Sex hormones, in particular, also control behaviors, and they influence mood. Animal models often provide important clues to the functions.



Summary of steroid hormones


A steroid hormone is a type of hormone that enters the cell and encounters and binds to its receptor in the cytoplasm or nucleus. The binding causes a change in the shape of the steroid receptor so that it can bind to DNA at sites to which it is appropriate. These can be very numerous - the estrogen receptor has over 20,000 binding sites. If binding occurs at essential gene regulatory DNA sequences, then genes regulated by this are transcribed into RNA in increased or decreased amounts (transcription is the name of the process). If this is mRNA and thus coding for a protein, then this usually results in increased or reduced synthesis of a protein. 'Less' or 'more' of an enzyme can change metabolism, for example. 'Less' or 'more' availability of a protein used as a building block of the cell can result in changes in cell metabolism or construction. 'Less' or 'more' can also determine whether a particular program is activated (e.g., anti-inflammation or cell protection). Sex hormones not only control development and fertility, but they also function in the brain and other organs.



Final words for You


Steroid hormones play a role in disease and are used as therapeutics. Keep in mind: If the adrenal cortex does not produce enough hormones after menopause, then it makes sense to add the missing hormone(s). Any doctor can determine this for you through blood analysis - the specialist is called an endocrinologist, which is often an additional training of gynecologists or internists. For example, estradiol is available as a gel or tablet, and progestin and DHEA-S (an androgen) in capsules. Here I am not referring to the treatment of menopausal symptoms but to maintaining the health of the body, which is at risk if steroid hormones are not adequately produced. This can affect both women and men and can occur if the function of the adrenal cortex begins to decline from middle age. Remember that progestins and other steroids protect nerve cells and might be necessary for preventing neurodegenerative diseases. Here it is essential to inform oneself more precisely if necessary.





















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