Dual function of DNA sequences: a new study shows that some are both coding and regulatory

Source: French to English Tester   Published on: 2026-04-29

Source: The Conversation – in French– By Benoit Ballester, Researcher in Bioinformatics at Inserm, Inserm Unit 1090 TAGC, Theories and Approaches of Genomic Complexity, Aix-Marseille University, Marseille., Aix-Marseille University (AMU)

For a long time, we have learned to read the genome by separating two worlds. On one side, the genes, those portions of DNA that contain the instructions to produce proteins. Inside these genes are the exons, the segments that directly serve to produce RNA and then proteins. On the other side, the regulatory DNA, often located inso-called non-coding regions, which controls where, when, and at what level genes are expressed. This boundary has been very useful. But it is more porous than previously thought.

In the study that we have just publishedinNature Communications, we show that thousands of exons, among the approximately 200,000 in the human genome, do not only serve to code proteins. Some of them also act as regulators, that is to say, sequences capable of stimulating gene expression. In other words, the same stretch of DNA can carry two messages at once: one for the protein, the other for regulation.

This idea already existed through some isolated examples, but our work proposes for the first time a systematic, large-scale view across several species, from human to mouse, including Drosophila and even a plant,Arabidopsis thaliana.

How did we answer this question?

This phenomenon was not entirely unknown. Since the 1990s,it was described in the scientific literature, over the course of specific cases or broader analyses, without really grasping the full extent.

To address this, we combined several large-scale approaches, leveraging very large volumes of biological data from previous work. We first analyzed more than 20,000 maps showing the locations in the genome where transcription factors bind, these proteins that control gene activity, in order to identify exons that resemble true regulatory regions.

We then looked for other evidence showing that these exons could really play a regulatory role. In particular, we checked whether they are located in the most accessible regions of DNA, a necessary condition for genes to be activated, and whether they are capable of increasing gene expression in functional tests. We also blocked some of these sequences in cells to see how their absence affected gene activity.

In the end, we identified more than 10,000 candidate exons in humans, with comparable signatures in the other species studied. This shows that this dual function is not an exception, but a widespread phenomenon in living organisms.

Why is it important?

This discovery first changes our understanding of gene regulation. Activating sequences were mainly sought in non-coding DNA, which accounts for 98% of our DNA. We show that part of this regulation is also embedded within the very heart of coding regions. Exons are therefore not only segments that produce proteins: some also participate in controlling gene expression, sometimes for their own gene, sometimes for other genes at a distance.

The issue is also medical. In genetics, a lot of attention is given to mutations that change the protein. But so-called synonymous mutations, often described as silent, are generally less considered. Indeed, the genetic code is read in groups of three letters, called codons, and several different codons can correspond to the same amino acid. In other words, a mutation can alter the DNA sequence without changing the produced protein. However, if an exon is also a regulator, a synonymous mutation can nonetheless disrupt a regulatory signal without directly altering the protein.

In our study, we show through functional tests that some of these variations indeed modify the regulatory activity of the exon. In data derived from tumors, we also observe that mutations located in these exons are associated with changes in the expression of target genes, including synonymous mutations.

What next steps should be taken for this project?

We are probably only at the beginning. The 10,000 exons identified in humans constitute an atlas, but not yet a complete map of all the biological contexts where these sequences function. The next step is therefore to test many more of them, in more cell types, tissues, and species, in order to understand when these exonic regulators are active, which genes they control, and how they emerged during evolution.

We will also need to broadly reconsider how we interpret variants located in exons. Until now, many analyses mainly asked: does this mutation change the protein? We must now also ask a second question: does it also change the regulation of the gene? This dual approach could refine the interpretation of variants that are still poorly understood, particularly in oncology and human genetics.

This work was supported by the MESR, INSERM, IFB, ANR.

–ref. Dual function of DNA sequences: a new study shows that some are both coding and regulatory –https://theconversation.com/double-function-of-dna-sequences-a-new-study-shows-that-some-are-both-coding-and-regulatory-280230