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Developing cells rely on genetic switches, DNA looping to become different tissue types, Stanford researchers find

DNA looping, or folding, directs a cell's developmental fate. Harnessing this 'DNA origami' could help researchers generate specific tissues for therapies.

It's been a biological conundrum for years. How does a stem cell early in development manage to make so many different tissue types using the same genetic ingredients? Researchers have known that transcription factors — proteins that stimulate the expression of particular genes — are a key component of this transition. But in many cases, one transcription factor can direct the creation of several cell types. So what confers the exquisite specificity necessary to drum up a developing embryo from a non-descript ball of cells?

Now dermatologist Anthony Oro, MD, PhD; postdoctoral scholar Jillian Pattison, PhD; former postdoctoral scholar Sandra Melo, PhD, and graduate student Samantha Piekos have deciphered how cells early in development can become a variety of tissues through the looping or folding of their DNA in response to master proteins called morphogens. They published their findings Monday in Nature Genetics.

From our release:

[Oro and his colleagues] have identified a key regulatory hierarchy in which proteins called morphogens control gene expression by directing the looping of DNA in a cell. This looping brings master regulators called transcription factors in contact with specific sets of genes necessary to make particular tissue types.

Varying concentrations and types of morphogens cause different looping events, directing different cell fates much in the same way that railroad workers control the direction and eventual destination of a train car by connecting different portions of track.

Learning how, why and when the DNA, or chromatin, folds is a key step in the ability to use cells as therapies, the researchers said. In particular, they are working to find new ways to generate function skin cells called keratinocytes to help people with a blistering, painful skin disease called epidermolysis bullosa. (I wrote about this quest, and the associated heartrending patient stories, in my magazine article "The Butterfly Effect" in 2015.)

As Oro explained:

Now we have the tools necessary to understand how the DNA folds and unfolds in response to changing conditions. Deciphering this chromatin origami is critical to learning how to make specific cell types for use in tissue replacement therapies... Making specific cell types is not a random event, and we can work to harness and accelerate this process to generate all kinds of transplantable tissues.

Photo by stantontcady

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