A New Approach to Understanding Enhancer-TF Interactions

Every cell in the human body contains the same DNA, yet liver cells are different from brain cells, and skin cells differ from muscle cells. What causes these differences? The answer lies in gene regulation—how certain genes are turned on or off to meet the specific needs of each cell. This process is complex, as various regions of DNA play a role in controlling which genes are activated or silenced.

Gene Regulators: Enhancers, Transcription Factors

The first crucial component that controls gene regulation is enhancers, which are tiny sections of DNA that boost the possibility that a gene will be activated, even if the gene is located far away in the genome.

The second are specialized proteins known as “transcription factors” (TFs), which attach to enhancers and, to put it simply, regulate gene expression by "flipping" the genes' on/off switches. TFs appear in a variety of forms, with current research estimating around 1600 of them in the human genome alone.

Enhancer “motifs”

Despite the importance of enhancers and TFs, scientists have struggled to understand how they work. Traditional techniques rely on what geneticists refer to as DNA "motifs": certain sequences or patterns of DNA that can be found across the genome, similar to an identifiable musical motif that appears in various portions of a symphony.

Currently, the approach is to identify enhancer patterns that highly effective TFs recognize. Nevertheless, it has not been able to account for the intricacy of gene regulation so far.

It appears that identifying these distinct motifs is insufficient; it is also important to consider the larger "enhancer context" in which these motifs are situated. This has prompted researchers to look for fresh approaches to comprehend how several TFs work together as enhancers to regulate gene expression.

A New Approach

Researchers led by Bart Deplancke at EPFL have now created a novel method for examining the interaction between enhancers and TFs. They discovered a novel class of "context-only" transcription factors (TFs) that appear to increase the activity of TFs that determine cellular identity, such as those found in the liver, blood, or brain.

Under the direction of Judith Kribelbauer, the study offers fresh insight into the cooperative settings that transcription factors (TFs) establish to control genes efficiently. The publication appears in Nature Genetics.

The results came from a type of genetic study known as "chromatin accessibility quantitative trait loci (caQTL) mapping," which the researchers employed. DNA sequence variants that are distinctive to a community are known as caQTLs. These variations affect the accessibility of a particular area of the genome to gene regulators like TFs, which in turn affects gene expression.

The group examined enhancers, including caQTLs, and determined the motif placement of several TFs. As a result, "context-only" TFs were identified; their name refers to the fact that these DNA motifs are located within the corresponding enhancer, adjacent to the caQTL.

The existence of ‘context-only’ TFs surprised us, as previous studies that looked into how DNA variation affects gene regulation focused on TFs that are directly affected by the caQT. Naturally, we were curious about what exactly these TFs do in the context of caQTLs, and whether they may play a role in deciding which of the numerous DNA mutations in our genomes affect gene regulation.”

Judith Kribelbauer, Postdoctoral Scientist, Swiss Federal Institute of Technology Lausanne

The study's results showed that even though context-only TFs do not directly start gene activity, they are still very important for amplifying the effects of caQTL-linked TFs that start changes in enhancer status; in other words, they help establish a cooperative environment that is more effective for regulating important genes.

Additionally, the researchers found that context-only TFs do not require physical proximity to the TFs they augment, indicating that their mode of operation may be more adaptable and dynamic than previously believed.

The discovery that context-only TFs could aid in the development of regulatory factor clusters—which are crucial for preserving cell identity—was another significant discovery. These groups can assemble into intricate networks of enhancers that cooperate to control gene expression, greatly varying the process to meet various biological requirements.

Scientists now have a better grasp of how genes are controlled in wellness and disease and how this regulation fails, for example, as a consequence of DNA mutations, which are common in complex diseases such as cancer.

The study also gives a framework for inferring how different TFs interact in diverse cellular scenarios, which might lead to more focused and effective genetic interventions, such as synthetic enhancer design.