In a recently published study, a team from the Centre for Genomic Regulation (CRG) and the National Centre for Genomic Analysis (CNAG) has shown that the so called distal genomic regulatory mechanism is active in non-bilateral animals such as sponges or comb jellyfish. This discovery suggests that this regulatory system appeared some 150 million years earlier than previously thought.
Distal regulation is the ability to control the expression of distant genes in the genome. Loops are formed that link genes together, activating expression. Until now, distal regulation was thought to occur only in bilateral animals, i.e. those with bilateral symmetry that divides the body into two identical halves. The CRG team’s finding indicates that it also occurs in genetically simpler animals with fewer DNA bases.
To find this, the researchers analysed the genome and its spatial arrangement both in some non-bilateral animals (such as sponges) and in their unicellular ancestors. While in the former, they found chromatin loops that bring promoter and enhancer genes closer together to activate the corresponding gene expression, in the latter, genomic regulation is only controlled linearly and at a short distance.
The study suggests that distal regulation would have appeared in an ancestor common to all animals. This, most likely a marine creature, would have evolved the ability to fold DNA in a controlled manner, creating the loops and bringing otherwise widely separated fragments closer together in space. According to Iana Kim, first author of the paper and affiliated with both the CRG and CNAG, ‘this creature could reuse its genetic toolkit in different ways, allowing it to refine and explore innovative survival strategies. We didn’t expect this layer of complexity to be so ancient.’
In addition, the team, led by Arnau Sebé-Pedrós (CRG), detected a substantial difference in the genetic structure of non-bilateral animals with respect to what was already known. In bilateral animals, chromatin loops are delimited by CTCF proteins that close them, as if they were a bow, and bring distal genes closer together. In contrast, they found that non-bilateral animals do not have this protein or an equivalent protein that performs the same function. ‘It is impressive that the same problem has been solved with different tools. Thanks to this work, we now know that two different proteins can be used to link distal pieces of DNA in space to form a loop,’ says fellow author Marc A. Marti-Renom, group leader of the CNAG and CRG.
This research helps to understand how genomic regulation evolved and could help detect which parts of it can go wrong most easily, which could translate into early detection of disease and development of new therapies.
Kim, I.V., Navarrete, C., Grau-Bové, X. et al. Chromatin loops are an ancestral hallmark of the animal regulatory genome. Nature (2025). https://doi.org/10.1038/s41586-025-08960-w
