How do you control over 20,000 genes?

Like a book with no one to read it, your DNA wouldn’t be very useful without transcription factors. These proteins interact with the DNA to help dictate what gets read, and what gets ignored. It is the action of these proteins that makes it possible for us to grow from a single cell into a complex being with skin cells, brain cells, and every other part of our bodies. Not surprisingly, variants in the DNA that disrupt the function of transcription factors can have a significant impact on our body.

Regulating when a gene is expressed—or when it’s read—is a critical activity in complex beings. Not every cell uses all 20,000 genes in the same way, so, it’s important for them to regulate how the DNA is used in order to prevent wasted energy and chaos. Cells have actually far exceeded a single form of gene regulation—there are numerous that we know about (like epigenetics) and likely more that we have yet to understand. But one of the most well-studied forms of regulation involves transcription factors.

The name “transcription factor” describes a diverse group of proteins who each share a common property: They can control gene expression through physical interactions with the DNA (also known as binding to the DNA). In essence, these proteins physically grab onto the DNA and either promote gene expression, or prevent it. In order for a gene to be expressed, a protein known as RNA polymerase must come to the gene, land on the DNA, and then start building an RNA sequence based on the DNA. For all of this to happen, there must be a sign that tells the RNA polymerase where it can land on the DNA. That’s the role of a transcription factor—it tells the RNA polymerase whether or not a gene is open for business.

Gene regulation demonstrated through animation.

Left: Transcription factor (green) binds to DNA and promotes transcription of RNA (green strand) by RNA polymerase (gray square). Right: Transcription factor (red) prevents gene expression.

 

The actions of transcription factors are determined by their physical shape and their chemistry. Proteins are built using amino acids, each of which has its own unique chemical and structural properties. When transcription factors are built, they form physical domains with the right combination of these properties to give them DNA binding abilities—specifically their given the ability to bind with specific segments of DNA. Remember that DNA itself is just a combination of nucleic acids which have their own structural and chemical properties. When a string of nucleic acids has the right combination of properties to match with those in the transcription factor, they’re able to interact. This is how transcription factors recognize specific sequences in the DNA.

A variant in the DNA is when at least one base pair changes, ultimately causing the DNA sequence to be slightly different from the reference genome. If this change occurs in a transcription factor binding domain, it can cause a change in the chemical properties of that DNA segment, and disrupt its ability to interact with a transcription factor. To put it more simply, changes in the DNA sequence can potentially change where transcription factors bind. This is a very important concept because it helps explain why some variants in the DNA affect gene expression, while others don’t.

Sequences of DNA that are recognized by transcription factors can be found throughout the genome. When these sequences happen to be located near a gene, it empowers those transcription factors to regulate that gene. When variants in the DNA disrupt a transcription factor binding site, it may cause the gene to go unregulated—meaning a cell won’t have as much control over when the gene is, or isn’t expressed.

It’s important to note here that, most of the time, gene regulation is not limited to a single transcription factor. For any given gene, there may be numerous transcription factors that are capable of regulating it. Some may try to stop the gene from being expressed, while others try to increase the gene’s expression. Whether a gene is expressed depends on the balance of negative and positive regulation. Variants in the DNA may alter this balance, and affect how a gene is expressed (or not expressed). As researchers discover new variants, they look to see if they could be disrupting a transcription factor’s ability to bind the DNA.

A good example of this is a variant in the DNA which affects regulation of the LCT gene—a gene partly responsible for digestion of lactose. The variant is believed to disrupt a promoter region near the LCT gene which may alter the regulation of the gene and affect a person’s ability to consume dairy products. Some DNA products actually test for this variant, including Insitome’s Metabolism, Everlywell’s Food Sensitivity+, Dot One’s ACGTote, and DNAPassport by Humancode.

In short, our bodies are kept in a strict balance, and transcription factors help make sure that we stay in that balance. They control when and where our genes are expressed. This organization allows us to grow skin cells which behave differently from liver cells and blood cells, among many others.

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