Overview: Eukaryotic gene regulation

How different genes are expressed in different cell types. The big picture of eukaryotic gene regulation.

Key points:

  • Gene regulation is the process of controlling which genes in a cell's DNA are expressed (used to make a functional product such as a protein).
  • Different cells in a multicellular organism may express very different sets of genes, even though they contain the same DNA.
  • The set of genes expressed in a cell determines the set of proteins and functional RNAs it contains, giving it its unique properties.
  • In eukaryotes like humans, gene expression involves many steps, and gene regulation can occur at any of these steps. However, many genes are regulated primarily at the level of transcription.

Introduction

Your amazing body contains hundreds of different cell types, from immune cells to skin cells to neurons. Almost all of your cells contain the same set of DNA instructions – so why do they look so different, and do such different jobs? The answer: different gene regulation!

Gene regulation makes cells different

Gene regulation is how a cell controls which genes, out of the many genes in its genome, are "turned on" (expressed). Thanks to gene regulation, each cell type in your body has a different set of active genes – despite the fact that almost all the cells of your body contain the exact same DNA. These different patterns of gene expression cause your various cell types to have different sets of proteins, making each cell type uniquely specialized to do its job.
For example, one of the jobs of the liver is to remove toxic substances like alcohol from the bloodstream. To do this, liver cells express genes encoding subunits (pieces) of an enzyme called alcohol dehydrogenase. This enzyme breaks alcohol down into a non-toxic molecule. The neurons in a person's brain don’t remove toxins from the body, so they keep these genes unexpressed, or “turned off.” Similarly, the cells of the liver don’t send signals using neurotransmitters, so they keep neurotransmitter genes turned off.
Left panel: liver cell. The liver cell contains alcohol dehydrogenase proteins. If we look in the nucleus, we see that an alcohol dehydrogenase gene is expressed to make RNA, while a neurotransmitter gene is not. The RNA is processed and translated, which is why the alcohol dehydrogenase proteins are found in the cell.
Right panel: neuron. The neuron contains neurotransmitter proteins. If we look in the nucleus, we see that the alcohol dehydrogenase gene is not expressed to make RNA, while the neurotransmitter gene is. The RNA is processed and translated, which is why the neurotransmitter proteins are found in the cell.
There are many other genes that are expressed differently between liver cells and neurons (or any two cell types in a multicellular organism like yourself).

How do cells "decide" which genes to turn on?

Now there's a tricky question! Many factors that can affect which genes a cell expresses. Different cell types express different sets of genes, as we saw above. However, two different cells of the same type may also have different gene expression patterns depending on their environment and internal state.
Broadly speaking, we can say that a cell's gene expression pattern is determined by information from both inside and outside the cell.
  • Examples of information from inside the cell: the proteins it inherited from its mother cell, whether its DNA is damaged, and how much ATP it has.
  • Examples of information from outside the cell: chemical signals from other cells, mechanical signals from the extracellular matrix, and nutrient levels.
How do these cues help a cell "decide" what genes to express? Cells don't make decisions in the sense that you or I would. Instead, they have molecular pathways that convert information – such as the binding of a chemical signal to its receptor – into a change in gene expression.
As an example, let's consider how cells respond to growth factors. A growth factor is a chemical signal from a neighboring cell that instructs a target cell to grow and divide. We could say that the cell "notices" the growth factor and "decides" to divide, but how do these processes actually occur?
Growth factors bind to their receptors on the cell surface and activate a signaling pathway in the cell. The signaling pathway activates transcription factors in the nucleus, which bind to DNA near division-promoting and growth-promoting genes and cause them to be transcribed into RNA. The RNA is processed and exported from the nucleus, then translated to make proteins that drive growth and division.
  • The cell detects the growth factor through physical binding of the growth factor to a receptor protein on the cell surface.
  • Binding of the growth factor causes the receptor to change shape, triggering a series of chemical events in the cell that activate proteins called transcription factors.
  • The transcription factors bind to certain sequences of DNA in the nucleus and cause transcription of cell division-related genes.
  • The products of these genes are various types of proteins that make the cell divide (drive cell growth and/or push the cell forward in the cell cycle).
This is just one example of how a cell can convert a source of information into a change in gene expression. There are many others, and understanding the logic of gene regulation is an area of ongoing research in biology today.
Growth factor signaling is complex and involves the activation of a variety of targets, including both transcription factors and non-transcription factor proteins. You can learn more about how growth factor signaling works in the article on intracellular signal transduction.

Eukaryotic gene expression can be regulated at many stages

In the articles that follow, we’ll examine different forms of eukaryotic gene regulation. That is, we'll see how the expression of genes in eukaryotes (like us!) can be controlled at various stages, from the availability of DNA to the production of mRNAs to the translation and processing of proteins.
Eukaryotic gene expression involves many steps, and almost all of them can be regulated. Different genes are regulated at different points, and it’s not uncommon for a gene (particularly an important or powerful one) to be regulated at multiple steps.
  • Chromatin accessibility. The structure of chromatin (DNA and its organizing proteins) can be regulated. More open or “relaxed” chromatin makes a gene more available for transcription.
  • Transcription. Transcription is a key regulatory point for many genes. Sets of transcription factor proteins bind to specific DNA sequences in or near a gene and promote or repress its transcription into an RNA.
  • RNA processing. Splicing, capping, and addition of a poly-A tail to an RNA molecule can be regulated, and so can exit from the nucleus. Different mRNAs may be made from the same pre-mRNA by alternative splicing.
Stages of eukaryotic gene expression (any of which can be potentially regulated).
  1. Chromatin structure. Chromatin may be tightly compacted or loose and open.
  2. Transcription. An available gene (with sufficiently open chromatin) is transcribed to make a primary transcript.
  3. Processing and export. The primary transcript is processed (spliced, capped, given a poly-A tail) and shipped out of the nucleus.
  4. mRNA stability. In the cytosol, the mRNA may be stable for long periods of time or may be quickly degraded (broken down).
  5. Translation. The mRNA may be translated more or less readily/frequently by ribosomes to make a polypeptide.
  6. Protein processing. The polypeptide may undergo various types of processing, including proteolytic cleavage (snipping off of amino acids) and addition of chemical modifications, such as phosphate groups.
All these steps (if applicable) need to be executed for a given gene for an active protein to be present in the cell.
Image based on similar diagrams from Reece et al. 1^1 and Purves et al. 2^2
  • RNA stability. The lifetime of an mRNA molecule in the cytosol affects how many proteins can be made from it. Small regulatory RNAs called miRNAs can bind to target mRNAs and cause them to be chopped up.
  • Translation. Translation of an mRNA may be increased or inhibited by regulators. For instance, miRNAs sometimes block translation of their target mRNAs (rather than causing them to be chopped up).
  • Protein activity. Proteins can undergo a variety of modifications, such as being chopped up or tagged with chemical groups. These modifications can be regulated and may affect the activity or behavior of the protein.
Although all stages of gene expression can be regulated, the main control point for many genes is transcription. Later stages of regulation often refine the gene expression patterns that are "roughed out" during transcription.
To learn more, see the articles on transcription factors and regulation after transcription.

Gene regulation and differences between species

Differences in gene regulation makes the different cell types in a multicellular organism (such as yourself) unique in structure and function. If we zoom out a step, gene regulation can also help us explain some of the differences in form and function between different species with relatively similar gene sequences.
For instance, humans and chimpanzees have genomes that are about 98.8%98.8\% identical at the DNA level. The protein-coding sequences of some genes are different between humans and chimpanzees, contributing to the differences between the species. However, researchers also think that changes in gene regulation play a major role in making humans and chimps different from one another. For instance, some DNA regions that are present in the chimpanzee genome but missing in the human genome contain known gene-regulatory sequences that control when, where, or how strongly a gene is expressed3^3.
This article is licensed under a CC BY-NC-SA 4.0 license.

Works cited:

  1. Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., and Jackson, R. B. (2011). Figure 18.6. Stages in gene expression that can be regulated in eukaryotic cells. In Campbell Biology (10th ed., p. 365). San Francisco, CA: Pearson.
  2. Purves, W. K., Sadava, D. E., Orians, G. H., and Heller, H.C. (2003). Figure 14.11. Potential points for the regulation of gene expression in eukaryotes. In Life: The science of biology (7th ed., p. 290). Sunderland, MA: Sinauer Associates.
  3. Kimball, John W. (2014, April 19). The human and chimpanzee genomes. In Kimball's biology pages. Retrieved from http://www.biology-pages.info/H/HominoidClade.html.

Additional references:

Alcohol dehydrogenase. (2016, January 6). Retrieved April 26, 2016 from Wikipedia: https://en.wikipedia.org/wiki/Alcohol_dehydrogenase.
Cooper, G. M. (2000). Regulation of transcription in eukaryotes. In The cell: A molecular approach. Sunderland, MA: Sinauer Associates. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK9904/.
Kimball, John W. (2014, April 19). The human and chimpanzee genomes. In Kimball's biology pages. Retrieved from http://www.biology-pages.info/H/HominoidClade.html.
OpenStax College, Biology. (2016, March 23). Eukaryotic transcription gene regulation. In _OpenStax CNX. Retrieved from http://cnx.org/contents/GFy_h8cu@10.8:7Ry3oRse@5/Eukaryotic-Transcription-Gene-.
OpenStax College, Biology. (2016, March 23). Regulation of gene expression. In _OpenStax CNX. Retrieved from http://cnx.org/contents/GFy_h8cu@10.8:dQV50wLv@7/Regulation-of-Gene-Expression
Phillips, T. (2008). Regulation of transcription and gene expression in eukaryotes. Nature Education, 1(1), 199. Retrieved from http://www.nature.com/scitable/topicpage/regulation-of-transcription-and-gene-expression-in-1086.
Purves, W. K., Sadava, D. E., Orians, G. H., and Heller, H.C. (2003). Transcriptional regulation of gene expression. In Life: The science of biology (7th ed., pp. 290-296). Sunderland, MA: Sinauer Associates.
Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., and Jackson, R. B. (2011). Eukaryotic gene expression is regulated at many stages. In Campbell Biology (10th ed., pp. 365-373). San Francisco, CA: Pearson.
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