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.
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.
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!
FAQs
What do gene regulatory networks do? ›
A gene regulatory network (GRN) describes the hierarchical relationship between transcription factors, associated proteins, and their target genes. Studying GRNs allows us to understand how a plant's genotype and environment are integrated to regulate downstream physiological responses.
What are regulatory networks for gene expression? ›A gene regulatory network (GRN) is a directed graph in which regulators of gene expression are connected to target gene nodes by interaction edges. Regulators of gene expression include transcription factors (TF) which can act as activators and repressors, RNA binding proteins, and regulatory RNAs.
What is the name of the regulatory sequence of DNA that controls when and how much RNA will be produced from that gene? ›Transcription factors are proteins that regulate the transcription of genes—that is, their copying into RNA, on the way to making a protein.
What happens if your DNA is altered? ›It is well established that changes in genes can alter a protein's function in the body, potentially causing health problems. Scientists have determined that changes in regions of DNA that do not contain genes (noncoding DNA) can also lead to disease.
What is a regulatory gene example? ›An example of a regulator gene is a gene that codes for a repressor protein that inhibits the activity of an operator (a gene which binds repressor proteins thus inhibiting the translation of RNA to protein via RNA polymerase).
How do gene regulatory proteins interact with DNA? ›Gene regulatory proteins recognize short stretches of double-helical DNA of defined sequence and thereby determine which of the thousands of genes in a cell will be transcribed. Thousands of gene regulatory proteins have been identified in a wide variety of organisms.
What are the three types of gene regulation? ›All three domains of life use positive regulation (turning on gene expression), negative regulation (turning off gene expression), and co-regulation (turning multiple genes on or off together) to control gene expression, but there are some differences in the specifics of how these jobs are carried out between ...
What are the two functions of gene regulatory proteins? ›Activators are regulatory proteins that promote transcription by enhancing the interaction of RNA polymerase with the promoter. Repressors are regulatory proteins that prevent transcription by impeding the progress of RNA polymerase along the DNA strand so the DNA cannot be transcribed to mRNA.
What regulates DNA access? ›The actions of most factors that regulate gene expression, including transcription factors, long non-coding RNAs, and others, are modulated by the underlying packaging of each eukaryotic gene into chromatin. The relative "openness" of chromatin controls the access of each of these factors to DNA.
What is gene regulation at DNA level? ›Regulation of gene expression can happen at any of the stages as DNA is transcribed into mRNA and mRNA is translated into protein. For convenience, regulation is divided into five levels: epigenetic, transcriptional, post-transcriptional, translational, and post-translational (Figure 17.6).
What destroys DNA in the body? ›
DNA can be damaged via environmental factors as well. Environmental agents such as UV light, ionizing radiation, and genotoxic chemicals. Replication forks can be stalled due to damaged DNA and double strand breaks are also a form of DNA damage.
Can DNA change in a person? ›Our DNA changes as we age. Some of these changes are epigenetic—they modify DNA without altering the genetic sequence itself. Epigenetic changes affect how genes are turned on and off, or expressed, and thus help regulate how cells in different parts of the body use the same genetic code.
Can your DNA mutate? ›Definition. A mutation is a change in the DNA sequence of an organism. Mutations can result from errors in DNA replication during cell division, exposure to mutagens or a viral infection.
What is the most common gene regulation? ›Sequence-specific transcription factors are considered the most important and diverse mechanisms of gene regulation in both prokaryotic and eukaryotic cells (Pulverer, 2005).
Why are regulatory genes so important? ›Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments.
What are the genes of the regulatory genes? ›Regulatory genes are those genes that code for proteins or factors that control the expression of structural genes. In prokaryotes, the structural genes of related functionality are usually present adjacent to each other and regulated by a single promoter and operator.
Do regulatory genes control structural genes? ›Structural genes encode proteins required for structural and functional uses. Regulatory genes encode factors that control the expression of structural genes.
Where do gene regulatory proteins bind? ›These proteins bind to regions of DNA, called regulatory elements which are located near promoters. The promoter is the region of a gene where RNA polymerase binds to initiate transcription of the DNA to mRNA. After regulatory proteins bind to regulatory elements, the proteins can interact with RNA polymerase.
What are the 4 stages of gene regulation? ›Control of gene expression in eukaryotic cells occurs at epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels.
What happens if regulatory gene is mutated? ›As described in this review, mutations in both positive (e.g. Mga) and negative (e.g. CovR) regulators of virulence factor expression are associated with phenotypic variation in GAS. These mutations can dramatically alter disease potential, from promoting invasive infections to promoting asymptomatic carriage.
Can the environment affect gene regulation? ›
Science tells us that the interactions between genes and environment shape human development. Despite the misconception that genes are “set in stone,” research shows that early experiences can determine how genes are turned on and off — and even whether some are expressed at all.
What is the difference between gene regulation and gene expression? ›The key difference between gene expression and gene regulation is that gene expression is a process that produces a functional protein or RNA from the genetic information hidden in a gene while gene regulation is the process that induces or represses the expression of a gene.
How does a gene get turned on? ›A gene is switched “on” when the portion of chromatin where it is located “opens.” This process involves proteins that add little chemical modifications to histones or to the DNA.
What turns DNA on and off? ›Epigenetics allows the muscle cell to turn “on” genes to make proteins important for its job and turn “off” genes important for a nerve cell's job. Your epigenetics change throughout your life.
What factors affect gene expression? ›Environmental factors such as diet, temperature, oxygen levels, humidity, light cycles, and the presence of mutagens can all impact which of an animal's genes are expressed, which ultimately affects the animal's phenotype.
How does DNA control you? ›The nucleotide sequences that make up DNA are a “code” for the cell to make hundreds of different types of proteins; it is these proteins that function to control and regulate cell growth, division, communication with other cells and most other cellular functions.
What controls DNA repair? ›These repair mechanisms are regulated by DNA damage response kinases including DNA-PKcs, ATM, and ATR that are activated at DNA lesions.
Does the government have access to your DNA? ›The CJIS is the FBI's home to biometrics, DNA, and other criminal information. Fingerprints help the government verify a security clearance applicant's criminal background. This is basic biometric information, and not applicant DNA.
What foods are good for DNA repair? ›Here's what to include: apples, mango, orange juice, apricots, watermelon, papayas, mangos and leafy greens are all high in nutrients shown to protect DNA. Blueberries are especially powerful; in one study, 10.5 ounces significantly lessened damage to DNA, in only an hour.
What is the most harmful DNA damage? ›DSB is one of the most critical and dangerous types of DNA lesions leading, if not repaired, to cell death.
What are 3 agents that can cause DNA damage? ›
Exogenous DNA damage, on the other hand, occurs when environmental, physical and chemical agents damage the DNA. Examples include UV and ionizing radiation, alkylating agents, and crosslinking agents.
How long does someone's DNA stay in another person? ›when you kiss your partner passionately, not only do you exchange bacteria and mucus, you also impart some of your genetic code. No matter how fleeting the encounter, the DNA will hang around in their mouth for at least an hour.
Can trauma change your DNA? ›Here's how: Trauma can leave a chemical mark on a person's genes, which can then be passed down to future generations. This mark doesn't cause a genetic mutation, but it does alter the mechanism by which the gene is expressed. This alteration is not genetic, but epigenetic.
Does stress change your DNA? ›Studies have shown that social stress can cause changes to the structure of DNA, with changes in DNA methylation and patterns of histone methylation and acetylation. These changes persist during cell division and are passed on to the daughter cells.
What genes are inherited from father only? ›All men inherit a Y chromosome from their father, which means all traits that are only found on the Y chromosome come from dad, not mom. The Supporting Evidence: Y-linked traits follow a clear paternal lineage.
Which cancers are hereditary? ›The cancers with the highest genetic contribution include breast, bowel, stomach and prostate cancers. Referral to a specialist cancer genetics service may be appropriate for people with a strong family history of cancer.
What genes are inherited from mother only? ›Unlike nuclear DNA, which comes from both parents, mitochondrial DNA comes only from the mother.
What is the role of a regulatory gene quizlet? ›What is the function of a regulator gene? A regulator gene produces a repressor protein, which is responsible for keeping genes turned off (and not expressed). The repressor protein must bind to the operator to keep an operon turned off.
What types of regulatory genes are there? ›All three domains of life use positive regulation (turning on gene expression), negative regulation (turning off gene expression), and co-regulation (turning multiple genes on or off together) to control gene expression, but there are some differences in the specifics of how these jobs are carried out between ...
What are two ways that genes are regulated? ›Specifically, gene expression is controlled on two levels. First, transcription is controlled by limiting the amount of mRNA that is produced from a particular gene. The second level of control is through post-transcriptional events that regulate the translation of mRNA into proteins.
Where exactly are the regulatory genes placed? ›
They are present upstream near the transcription start sites of genes in between the operator and structural gene. Regulatory gene regulates the expression of structural genes by its protein products that are mostly transcription factors.