Around one in every 1,000 babies born every year has Down Syndrome – a condition caused by inheriting an extra segment of DNA, known as a chromosome. Humans usually have 23 pairs of chromosomes, numbered one to 22 plus the sex chromosomes (XX or XY). We get one of each pair from our mother and the other from our father. But in the case of Down Syndrome babies, they end up with an extra copy of chromosome 21, meaning they have a triple dose of all the 500 or so genes on that chromosome.
It’s just one of these genes – called DYRK1A – that interests Susana de la Luna, leader of the Gene Function group at the CRG. For some human genes, having an extra copy doesn’t seem to matter. But the extra ‘dose’ of DYRK1A in Down Syndrome causes problems for cells. Similarly, if a child has only one functional copy of the gene, effectively halving the dose, they end up with an autism-like condition as well as other health issues. De la Luna and her team are trying to find out why.

Get set

Genes are molecular ‘recipes’ that tell cells how to make protein molecules, which do all kinds of jobs in the body from forming strong structures like the skin to breaking down food to release energy. DYRK1A makes a type of protein called a kinase (also referred to as DYRK1A), which sticks tiny chemical tags onto other proteins and either triggers them into action or switches them off.

“We want to understand the molecular mechanisms that underlie the problems caused by three or one copy of DYRK1A,” says de la Luna, “so we need to know the targets of the kinase, and what happens when there is too much or not enough of it.”

The first clue came when de la Luna and her team discovered DYRK1A kinase in the nucleus of cells, where the DNA is kept. Looking more closely, they discovered DYRK1A is directly bound to DNA and its associated packaging proteins (known collectively as chromatin), homing in on characteristic sequences of DNA.

The next part of the puzzle was revealed when the researchers discovered that DYRK1A had a potent activating effect on nearby genes, strongly switching them on. And the final clue slotted in to place when they found that the kinase was ‘tagging’ an important part of RNA polymerase, the molecular machine that ‘reads’ genes when they are switched on and active, like reading a recipe in a cookbook.


In order to read a gene, RNA polymerase finds the start of the ‘recipe’ and waits there, loading itself up with all the proteins it needs to work properly. Then when everything is ready, DYRK1A adds its tags, providing the final trigger for the polymerase to start moving along the gene, reading as it goes.

“It was very surprising to discover that DYRK1A sits on chromatin at genes with these particular sequences in the ‘control switches’ near genes, and can directly tag the polymerase,” explains de la Luna. “Not many kinases are known to do this.”

Careful analysis revealed that many of the genes targeted by DYRK1A are involved in helping cells to grow – for example, by making energy or manufacturing more proteins. De la Luna suspects that this may help to explain why having too much or too little of it causes problems.

“In the case of Down Syndrome there are other genes on chromosome 21 with increased activity which can also contribute to cells not working properly, but we think the new role we have found for DYRK1A role has something to do with the effects we see in children with Down’s or the autism syndrome.”

This paper, published in the journal Molecular Cell, raises many more questions than it answers, providing a lot more work for de la Luna and her team still to do.

“Much of this work was done by Chiara Di Vona,” she says, highlighting her PhD student’s vital role in the study and other collaborators Nuria Lopez-Bigas and her team at Pompeu Fabra University and Stephan Ossowski’s lab at the CRG.

“It was a risky project with technical challenges, but it paid off. This is a paper about basic biology, so there is still a long way to go to explain how the changes in this gene cause disease. There are also still many questions, but this work opens an exciting door to a place where there is a lot to explore and where we might find solutions to improve the outcome for people affected by these conditions.”