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'Neurons can't get notions of being muscles': What makes cells with the same DNA act differently?

“Imagine your genes are books in a library…”

Image: Shutterstock/vchal

IRISH RESEARCHERS HAVE discovered new proteins that aid in deciding how cells develop.

Although studies have already identified the main proteins that direct and restrict cells in the early stage of development so that they acquire a specific function, (such as neuron, muscle, or skin cells), researchers at Trinity College Dublin have found a ‘new family’ of proteins that are crucial for this process during embryonic development.

To point out their importance, the researchers say that if these proteins are removed, the animal dies. Added to that is the fact that these new proteins are only present in animals with vertebrae such as fish, reptiles and mammals.

Each human has hundreds and hundreds of different types of cell, with the same DNA in each of those cells. Despite each cell type containing a carbon copy of the DNA/genes of all other cells in the body, you can’t turn on genes needed to be a neuron in a muscle cell, and you can’t turn on genes needed to be a muscle in a skin cell or things go awry.

Associate Professor of Genetics Adrian Bracken cut through the intricacies of the science of epigenetics to a more digestible explanation of what goes on when your cells are developing, what exactly they’ve discovered and why it matters.

“Imagine your many thousands of genes are books in a library, and you can read these genes (or books),” he says.

“This library has all the information to do anything, but if you’re an engineer, you’ll just go to the section about engineering, and if you’re a scientist you’ll go to the science section, and if you’re a plumber you’ll go to the plumbing section.

“So imagine the scientist is a neuron cell and the plumber is a skin cell. The strict librarian will tell the scientist that all the books except the ones in the science section are blocked off for them. If you’re developing into a neuron, that’s fine – you can access all the genes you need to be a neuron.”

The ‘librarian’ in this analogy is an epigenetic protein called polycomb; as part of their research, Bracken and his associates have discovered another family of polycomb proteins called PALI1 and PALI2, which are only present in vertebrae. Bracken explains what they do.

“Continuing the analogy, and considering we have many more different types of cells in
more complicated animals, there is not just an engineer, there’s also a mechanical engineer, so they can’t access books related to electronic or civil engineering. So we’ll say there are other, even more strict librarians in the library to enforce that.”

He says that those two new polycomb proteins are vital for development – in tests where they knocked them out, the mouse died at the end of embryonic development.

“This shows that they’re integral,” Bracken says.

If the polycomb proteins aren’t doing their job, it also has consequences.

“On a particular day, the very strict librarian might not be doing their job properly, so you’re allowed to read books (or genes) you shouldn’t be, which means it becomes chaotic in the library.”

Suddenly cells lose their identities and you have a big problem.

This is the case in many cancers: the identity of cells are lost and they don’t mature or develop to their specialised role as an ’adult’ cell.

Neurons can’t get notions of a career change and become a muscle cell.

Well, not on their own they can’t.

There’s been Nobel Prize winning work that showed that it is possible to take a skin cell and turn it back into a stem cell, or even turn them into a neuron from there.

“It’s not science fiction to say someone could turn your skin cell into a blood cell, so that’s an exciting field in stem cell biology,” Bracken says, but when loss of cellular identity happens in a human being, there are serious and sometimes deadly consequences.

For example in diseases such as B-cell lymphoma, gene mutations can cause the polycomb proteins not to perform in the correct way.

“If you’re a blood cell, it’s important not only that you turn on the genes you need to be a blood cell, but turn off the genes you don’t need.

So if the strict librarian suddenly isn’t doing their job, they’re coming into work but not working, saying ‘I dunno, do whatever you want’, then the cell gets totally confused and doesn’t become a mature functioning blood cell – and can then be stuck in a cancerous state.

Another cancer-type related to the loss of polycomb function is Diffuse Intrinsic Pontine Glioma (DIPG), which is the second most common type of primary high-grade brain tumour in children.

Bracken says that loss of polycomb function causes these certain types of brain cells, called glial cells, to lose the ability to mature and then leads them to “diffuse” through the child’s brain. It’s often fatal.

“We’ve been awarded funding from the Worldwide Cancer Research Fund and Science Foundation Ireland to do further research into DIPG and B-cell lymphomas.”

His team is hoping that their research on polycomb proteins will help lead to the development of new treatments for patients with these types of cancer.

“So, studying the function of polycomb proteins such as PALI1 and PALI2 is not just academically interesting in terms of understanding cellular identity and epigenetics, but it has real consequences as well.”

Genetic research at Trinity College Dublin is also funded by Irish Cancer Society, the Irish Research Council, and the Health Research Board.

You can find out more about that research here.

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