The genetic sergeants that keep stem cells stemmy

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Stem cells are bursting with potential. They can produce every type of cell in the human body. Small clumps of them can generate entire individuals. But this ability, known as pluripotency, is hard won. So stem cells must constantly repress genetic programmes that threaten to send them down specific routes, and rob them of their limitless potential. “Imagine you’re a stem cell,” says Mitchell Guttman from the Broad Institute of MIT and Harvard. “The worst thing that could happen is that you accidentally turn on, say, neural genes and become a brain cell.”

Now, Guttman has found that stem cells keep themselves ‘stemmy’ with a group of genes called lincRNAs. His discovery not only assigns an important role to these mysterious genes, it opens up a new potential way of precisely controlling what goes on inside a cell.

The “central dogma of biology” says that DNA stores information, which is copied into a related molecule called RNA. That information is used to build proteins, which go about the cell doing important jobs. But this description only applies to a minority of our genome. At least 98 percent of our DNA doesn’t create proteins at all, but some of this “non-coding” chunk is still converted into RNA. These non-coding RNAs come in many shapes and sizes, and Guttman focused on a group of particularly large ones called lincRNAs. We have thousands of them and until now, we knew very little about what they do.

One of them switches off a copy of the X chromosome in the cells of women. But aside from a handful of such examples, the role of lincRNAs has been shrouded in mystery. Some scientists have suggested that they’re mostly genetic scrap, produced when our cells copy more useful bits of information from nearby genes. But in 2009, Guttman found that many lincRNAs have changed very little as mammals evolved, and they seem to interact with important genes and proteins in our cells. They really looked like they were doing something.

To find out what, Guttman did what most geneticists would do – he got rid of the lincRNAs, one at a time, in the embryonic stem cells of mice. Around 95 percent of lincRNAs caused a profound shift in the activity of other genes when they disappeared. Guttman also found that a smaller group – around 10 percent – is responsible for keeping stem cells in a pluripotent state.

They do this in two ways. Some maintain the status quo – they control the activity of genes such as Nanog, which are necessary for maintaining the stem-like state. Others hold back change – they repress genes that would convert stem cells into more specific types, such as muscle or liver cells or neurons. This latter group are very specific – most target a single programme and keep it in check. Without the combined efforts of these lincRNAs, Guttman’s stem cells started changing into more specialised types.

Of course, we already know about many proteins that keep stem cells the way they are, acting together in large cooperative complexes. The lincRNAs aren’t just doing the same job in a different guise Instead, Guttman found that many lincRNAs (living up to their names) form physical bridges between different protein complexes. He thinks that they might be helping to coordinate the proteins.

“Controlling pluripotency is a battle,” he says. “Proteins are like the soldiers in this battle. They can do many different things but they need their orders. The lincRNAs are the sergeants that coordinate the proteins into a coherent response.”

Controlling stem cells is probably just the tip of the iceberg. There’s still a lot to learn about what lincRNAs do. As Guttman showed, most of them affect the activity of many genes beyond those involved in stem cells. “Any time you need coordinated effort in the cell, you can imagine that a lincRNA might be able to bring together the right players for the job,” says Guttman.

This discovery could help scientists to reliably convert stem cells into different tissues and organs of interest. That’s a necessary step towards creating bespoke organs – a major goal of medical biology. Switching off the relevant lincRNA could make that task easier. “You need to understand the important parts of how cells are wired in order to control them,” says Guttman. “We’ve been missing this whole critical piece for a long time.”

But Guttman thinks that the biggest potential application of his work comes from the knowledge that lincRNAs can act as bridges for different protein complexes. “Once we’ve learned all the rules, we can imagine engineering artificial RNAs that can bind to specific proteins we care about, to target specific genes in specific ways.” We can give the sergeants their marching orders.

Reference: Guttma, Donaghey, Carey, Garber, Grenier, Munson, Young, Lucas, Ach, Bruhn, Yang, Amit, Meissner, Regev, Rinn, Root & Lander. 2011. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature

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