Number of genes and their repressors

[Eagle9]

Good day guys

I want to clarify one issue in molecular biology.

As well-known a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers.

The number of genes in human genome is about 20 000, so how many repressors do we have? The same 20 000? In other words, does every single gene have strictly corresponding repressor? Second question: if some certain gene is turned off (by means of repressor) how can we turn it on? Can we selectively remove this repressor? Or should we turn that gene off that codes that repressor?

 

[BillTre]

The number of genes in human genome is about 20 000, so how many repressors do we have?

Probably only approximations are known.
The functions of all gene are not yet known.

does every single gene have strictly corresponding repressor?

Not usually.
Repressors (as well as things that turn genes on) are often promiscuous.
When considering issues like this, it is probably beneficial to consider not only the the negative regulators, but also the positive ones.
They often work in combination and can have complex interactions that can produce complicated responses.
A single type of regulatory molecule can affect the activity of many genes.
Many genes are regulated by several regulatory molecules.
Some negative regulatory molecules can affect large chromosomal areas, shutting down transciption from a whole genomic area.

Second question: if some certain gene is turned off (by means of repressor) how can we turn it on? Can we selectively remove this repressor? Or should we turn that gene off that codes that repressor?

Genes can get turned off.
Other molecules could out compete the repressor for binding sites where the repression is be effected.
I am sure there are other mechanisms I am not thinking of right now.

In metazoan (animal) development, there is a cascade of changes in gene regulation, as the regulation of both regulatory genes and other genes changes.
Individual cells transition from a zygotic (fertilized egg cell) cell, to cells in various stages of embryology, before ultimately reaching the reproductive adult stages.
In each of these cells, different sets of genes are activated, producing different products (including regulator proteins and RNAs).

You probably want to read up on gene regulation to learn more. Wikipedia entry.
There are lots and lots of details.
It is mechanistically very complicated.

 

[jim mcnamara]

Another source of gene regulation is environmental - epigenetics. It also appears to be important in cell differentiation - e.g., single celled zygote developing into a newborn human with billions of cells and many tissues with widely varying functions and active genes.

The primary operational mode is methylation of DNA strands - sometimes histones play a role here, too.

It is not necessarily like a simple off/on switch -- as you referenced. Sometimes it merely slows down transcription; called down regulation. The reverse is up regulation.

Technical list of known DNA chemical interactions:
https://www.genome.gov/about-genomics/fact-sheets/Epigenomics-Fact-Sheet

Here is a start on learning about it, aimed at folks with less science background than the above link:

https://www.whatisepigenetics.com/fundamentals/

Do not get too wrapped up in some claims made there. Not all papers merit life style changes, for example.

It is somewhat self-promotional, but the information is reasonable.

On the plus side: There is floating banner showing a stream of recent papers. You could easily spend hours reading everything.

 

[docnet]

The number of genes in human genome is about 20 000, so how many repressors do we have? The same 20 000? In other words, does every single gene have strictly corresponding repressor?

A model of the operon that consists of a promoter, operator, genes, and a repressor is a simplified picture of prokaryotic gene regulation. The real picture is more complex, for example, a region that codes for one gene can also serve as a repressor or enhancer for others.

simplified picture of prokaryotic DNA:

_______promoter______operator______genes_________repressor___
The following diagram is a simplified picture of human gene regulation.

The human gene regulation is more complex. For example, there are many transcription factors that interact with each other and regulate multiple genes (corresponding to other transcription factors or target genes), and most interactions are unknown.

The following diagrams may give an idea of the number of interactions involving several transcription factors.

Second question: if some certain gene is turned off (by means of repressor) how can we turn it on? Can we selectively remove this repressor? Or should we turn that gene off that codes that repressor?

I believe the answer is yes, to both of your questions.

 

[Eagle9]

The functions of all gene are not yet known.

Of course

Not usually.
Repressors (as well as things that turn genes on) are often promiscuous.
When considering issues like this, it is probably beneficial to consider not only the the negative regulators, but also the positive ones.
They often work in combination and can have complex interactions that can produce complicated responses.
A single type of regulatory molecule can affect the activity of many genes.
Many genes are regulated by several regulatory molecules.
Some negative regulatory molecules can affect large chromosomal areas, shutting down transciption from a whole genomic area.

Genes can get turned off.
Other molecules could out compete the repressor for binding sites where the repression is be effected.
I am sure there are other mechanisms I am not thinking of right now.

In metazoan (animal) development, there is a cascade of changes in gene regulation, as the regulation of both regulatory genes and other genes changes.
Individual cells transition from a zygotic (fertilized egg cell) cell, to cells in various stages of embryology, before ultimately reaching the reproductive adult stages.
In each of these cells, different sets of genes are activated, producing different products (including regulator proteins and RNAs).

You probably want to read up on gene regulation to learn more. Wikipedia entry.
There are lots and lots of details.
It is mechanistically very complicated.

Thanks, I see that this (whole) situation is quite complex

jim mcnamara
Thanks

The real picture is more complex, for example, a region that codes for one gene can also serve as a repressor or enhancer for others

I hear this first time, thanks

I believe the answer is yes, to both of your questions.

Oh, it turns out to be much more difficult than I expected

I believe the answer is yes, to both of your questions.

Thanks, however I believe it would be very difficult to do in practice

 

[Eagle9]

Eagle9

if some certain gene is turned off (by means of repressor) how can we turn it on? Can we selectively remove this repressor? Or should we turn that gene off that codes that repressor?

I believe the answer is yes, to both of your questions.

Could you please tell me how the repressor can be removed from DNA? Is there such example (at least one) in biotechnology?

 

[Ygggdrasil]

Here's a PF thread discussing such an example: https://www.physicsforums.com/threa...chnologies-wont-lead-designer-babies/']crispr-against-blood-diseases.997005/[/URL]

The BCL11a transcription factor represses expression of the gamma globulin gene. Scientists used different gene therapy approaches (shRNA or CRISPR) to inactivate the BCL11a gene, which resulted in re-expression of the gamma globulin gene.

 

[Eagle9]

Here's a PF thread discussing such an example: https://www.physicsforums.com/threa...chnologies-wont-lead-designer-babies/']crispr-against-blood-diseases.997005/[/URL]

I will read this thread a bit later, but now:

The BCL11a transcription factor represses expression of the gamma globulin gene. Scientists used different gene therapy approaches (shRNA or CRISPR) to inactivate the BCL11a gene, which resulted in re-expression of the gamma globulin gene.

In my question I meant a bit different thing namely: imagine that some certain repressor is physically attached to DNA (I am dealing with neuroscience, I am not expert in molecular biology but as far as I remember many repressors are attached to genes and these genes cannot be transcribed). So, this repressor was once created (transcription+translation), then it attached to gene and stays there, so can it be physically removed from there? Can some nanorobot hit, decompose it or something like this.

The BCL11a transcription factor represses expression of the gamma globulin gene

So, this molecule BCL11a is transcription factor for some other gene but at the same time it serves as repressor for gamma globulin gene? Such situation is frequent in genetics?

 

[Ygggdrasil]

In my question I meant a bit different thing namely: imagine that some certain repressor is physically attached to DNA (I am dealing with neuroscience, I am not expert in molecular biology but as far as I remember many repressors are attached to genes and these genes cannot be transcribed). So, this repressor was once created (transcription+translation), then it attached to gene and stays there, so can it be physically removed from there? Can some nanorobot hit, decompose it or something like this.

A repressor (R) binds reversibly to DNA through non-covalent interactions to form a repressor-DNA complex (R-DNA):
$$ \text{R} + \text{DNA} \rightleftharpoons \text{R-DNA}$$
If you eliminate transcription of the repressor, the concentration of free repressor should decrease (either through dilution over cell replication or degradation of the repressor molecules over time), which decreases the amount of R-DNA complex. No special mechanisms are needed in most cases to disassemble a R-DNA complex. This process can be slow, but work well in rapidly dividing cells (such as those modified in the BCL11a example). There are other methods to more rapidly degrade repressor proteins.

So, this molecule BCL11a is transcription factor for some other gene but at the same time it serves as repressor for gamma globulin gene? Such situation is frequent in genetics?

A transcription factor is a general term for a molecule (usually a protein) that regulates transcription. This regulation could be either activation of transcription or inhibition of transcription (and sometimes a TF can act as a repressor in some contexts and an activator in other contexts). Here's Wikipedia's definition of a transcription factor:

In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence.[1][2] The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the right cell at the right time and in the right amount throughout the life of the cell and the organism.

https://en.wikipedia.org/wiki/Transcription_factor

 

[Eagle9]

If you eliminate transcription of the repressor, the concentration of free repressor should decrease (either through dilution over cell replication or degradation of the repressor molecules over time), which decreases the amount of R-DNA complex. No special mechanisms are needed in most cases to disassemble a R-DNA complex.

Thanks, I wanted to know exactly this

There are other methods to more rapidly degrade repressor proteins

And which ones?

A transcription factor is a general term for a molecule (usually a protein) that regulates transcription. This regulation could be either activation of transcription or inhibition of transcription (and sometimes a TF can act as a repressor in some contexts and an activator in other contexts). Here's Wikipedia's definition of a transcription factor:

Thanks, now it is clear

 

[Ygggdrasil]

And which ones?

If it's possible to genetically tag the protein of interest, a common approach is to use a degron tag. This is essentially adding a short polypeptide sequence to the protein that will target the protein for degradation under specific conditions. For more extensive discussion see: https://www.annualreviews.org/doi/pdf/10.1146/annurev-genet-120116-024656

If genetic tagging is not possible, one can use a PROTAC strategy. A PROTAC is a small molecule drug that will bind to the target protein of interest and cause the protein to be degraded by the cell. For more extensive discussion of this approach, see: https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00597

 

[Eagle9]

Ygggdrasil
Thanks