by Samantha Royle
figures by Allie Elchert

Have you ever thought about how a single cell can grow into a living, breathing, human? The extraordinary complexity of our thinking brains, wiggling fingers and beating hearts emerges from a single celled zygote, formed from the fusion of egg and sperm. Many of us have heard of DNA, the molecule that contains the instructions for life, but have you ever considered how DNA can control human development? All of the instructions for the human body are contained in one cell! While scientists are still working to understand every step of the process, we now know how this amazing feat of nature can occur, and it’s all thanks to gene regulatory networks (GRNs). 

From genes to proteins: how selective expression determines cell identity 

The entire human genome contains around 19,000 genes. Each one of your cells contains all of these genes, but not all of them will be ‘expressed’, or turned on, in every cell. The genes that a cell is expressing determine the cell’s type, shape, and behaviour. For example, heart cells express one subset of genes, while lung cells express a different set of genes, and skin cells express yet another set of genes. This selective use of genes is what allows for the immense diversity of cell types that compose the human body. 

A gene is a discrete unit of DNA that provides the instructions for making a specific protein, meaning the gene tells the cell how to assemble chemical building blocks to make a large, complex molecule. These complex protein molecules carry out numerous and varied functions in the body. One protein you may have heard of is collagen, which is required for skin, hair, and bone formation. There are 28 different types of collagen protein, each with a different corresponding gene. The thousands of other proteins that our bodies require to function on a daily basis are each coded for by their own respective genes.

How do cells know whether they should be turning on the genes for bone formation, or heart formation? How does a cell know whether it’s in the finger or the chest? The answer is that not all genes in the genome code for  proteins that build and run the body – some genes code for proteins whose function is to tell other genes whether to turn on or off. These genes can be connected in huge networks that are crucial for setting up complex interactions between cells and tissues during development and beyond. 

A Quick primer on GRNs

Gene regulatory networks are a way of describing how genes can turn each other on and off. A simple gene regulatory network could be one in which Gene A produces a protein which turns on Gene B, which itself produces a protein which turns on Gene C (Figure 1, part 1)s). This might seem somewhat redundant – why doesn’t Gene A just make a protein which directly turns on Gene C? The extra step allows there to be some finer tuning in the levels of protein that Gene B and C produce. Perhaps a certain amount of Protein A needs to be produced before Gene B turns on, or there are multiple inputs into Gene C – not only Gene B, but also Genes X, Y and Z (Figure 1, part 2)). For example, one gene called OCA2 is important in determining eye color. If less of the protein coded for by OCA2 is produced, a person’s eyes will be blue, but if a lot of OCA2’s protein is produced, a person’s eyes will be brown. The level of OCA2 is controlled by a gene, and its associated protein, called HLTF. However, there are many other genes which are involved in eye colour, and it is the integration of all of these inputs which leads to the wide spectrum of eye colours we see in humans. Gene regulatory networks allow complex inputs from different sources in a cell to be integrated.

Figure 1. Gene regulatory networks: Gene regulatory networks (GRNs) can be schematized using arrows with pointed and flat ends to show how genes affect each other. A pointed arrow (→) indicates that the protein product of one gene turns another gene on. A flat headed arrow (⊣) indicates that the protein product of one gene turns another gene off. In all of the parts of this figure, the left hand schematic shows how the genes interact whilst the graph on the right shows how the levels of gene expression (y-axis) change over time (x-axis). (1) Expression of Gene A leads to Gene B being turned on, which eventually leads to Gene C turning on when enough protein from Gene B has been produced. (2) Gene C is not expressed until both Gene B and Gene X are producing protein. (3) The protein products of Gene B and C turn on the other genes. This leads to a Positive Feedback Loop. (4) Gene expression can be made to Oscillate if the genes regulate each other in the way shown in part 4. Whenever levels of B increase, levels of C increase and cause the levels of B to decrease again.

These regulatory networks can start to get more complicated if Gene C begins to affect the expression of Gene B (Figure 1, part 3). If Gene C causes Gene B to be expressed then a positive feedback loop can be established, and the levels of both genes will increase exponentially as each gene continues to increase the expression of the other. This reinforcement can help push a cell down a particular pathway if a minimum level of Gene B is required before a cell takes on a certain identity. For example, small random fluctuations in expression of certain genes called Notch genes lead to positive feedback loops that push the cells of the head to become muscle or gut tissue.  

On the other hand, if Gene C inhibits Gene B, or prevents it from being expressed, then the level of B and C will decrease over time. One interesting pattern is when Gene A remains on – this can allow oscillations to occur. If Gene C turns off Gene B, then once both genes are turned off, A will begin to induce Gene B again, raising levels of B and C until C is high enough to start inhibiting B and the cycle starts over (Figure 1, part 4). Oscillating genes can control the circadian rhythms that influence the state of our body throughout the day, making us tired at night and awake in the morning. Gene interactions can be incredibly complicated and even a simple network of three genes interacting can allow cells to respond to cues in complex ways.

GRNs in development

Expressed genes can regulate other genes and cause a cell to change its present or future state, but that does not explain the complex patterns we see in nature. For there to be organisation of cells into larger structures, such as animals, the cells need to be able to interact with each other. Cells do this by releasing proteins which influence surrounding cells. Proteins bind to the surface of the neighbouring cells and trigger a change in gene expression of the nearby cell. How then, do GRNs lead to the formation of a human body from a single cell? The answer is that, over time, the embryo is gradually split into an increasing number of developmental compartments with their own gene regulatory networks. These developmental compartments lead to organ systems such as the respiratory system. Each organ system can be split into smaller compartments, called organs. For example, in the respiratory system, these include the lungs, the airways, and the blood vessels. The early cells in an embryo have almost limitless possibilities  to become any type of cell, and as they divide, small differences in gene expression in the daughter cells causes the daughters to take on more specific fates. The fate of a cell describes its future identity, or the identity of its daughter cells. Cells can interact to push each other towards various fates, and this sets up different regions of the embryo that go on to form the different organ systems. The cell’s descendants become more limited in their fate over time, from an organ system to an organ, to a particular cell type within that organ. So, for example, a cell is first limited to being in the emerging body, rather than the mother’s placenta, then its descendants could ultimately become limited to the gut. From there, the network of genes could push the cell’s descendants to become a specialised cell for producing enzymes for digestion.

Figure 2. A cell’s fate becomes more restricted over time: Early on in development, the cells have lots of potential to become any organ in the body. Over time, the descendants of the cell are confined to an organ system and then an organ. This figure illustrates one possible route for a cell and its descendants.

GRNs continue to control how your cells interact throughout life. Once you are born, your cells don’t stay the same forever – they continue to divide, specialize, and influence each other. The genes that cells express continue to govern the cell’s properties throughout life, and so understanding how these genes interact in networks may be crucial for better understanding diseases. In fact, when cells activate the wrong GRNs, this can lead to cancer. Up until recently, our understanding of GRNs mainly covered early aspects of development where there are few cell types and not much variation in embryos. However, as computational power increases, we are able to model the interactions of many more genes in much more detail. Moving forward, this will give us a much more detailed understanding of development and disease, and could be crucial in developing therapeutics in the future.

Samantha Royle is a 5th year PhD student in the Organismic and Evolutionary Biology program, and works at Harvard Medical School.

Allie Elchert is a third-year Ph.D. candidate in the Biological and Biomedical Sciences program at Harvard Medical School.

Cover image by Arek Socha from Pixabay

For More Information:

  • For a deep dive into the best known GRN in development, gut formation in a sea urchin, check out this review.
  • For an exploration of how GRNs may be implicated in evolution, read this article.
  • This article describes how gene regulatory networks can generate complex patterns.
  • Finally, this is a review of how gene regulatory networks have been implicated in disease so far.

This article is part of our special edition on networks. To read more, check out our special edition homepage!

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