In a breakthrough that could lead to a more efficient way of generating therapeutic cell lines, Harvard and MIT researchers have recently discovered the critical role of a set of genetic elements, known as large intergenic noncoding RNAs, in cellular reprogramming.
These findings, which show for the first time the importance of lincRNAs in deriving induced pluripotent stem cells, could better scientists’ understanding of stem cell reprogramming, which reverts cells to their embryonic-like state to be then turned into a different type of tissue.
LincRNAs are essential regulators of cellular reprogramming, but their effects are still poorly understood, leading John L. Rinn, a senior author of the study, to describe them as “the dark matter of the genome.”
To generate pluripotent cells, researchers introduce what is known as a “cocktail” of four transcription factors into adult cells. These factors, which drive the reprogramming process, generate induced pluripotent stem cells.
The mechanism underlying how these factor drive the process is poorly understood, according to Rinn, an assistant professor of stem cell and regenerative biology at the Harvard Medical School.
In the study, the researchers detected elevated levels of lincRNAs in induced pluripotent stem cells, and found that the lincRNAs are also targeted by pluripotency reprogramming factors.
“We know the general architecture with the four ‘cocktail’ proteins, but we didn’t know the sub-circuitry,” said Rinn. “We have found new wires on the circuit board.”
Rinn said that he and his fellow scientists were surprised by the finding that lincRNAs not only were required for reprogramming, but enhanced the process.
In fact, using lincRNAs increased the success rates of the reprogramming process up to eight times, compared to existing methods that do not use these molecules.
This finding may have significant implications for developing therapeutic interventions, Rinn said.
The next step, he said, is to study the progress in reverse and to understand lincRNAs’ role in facilitating cellular differentiation.
“[This work] has opened up a new area that needs to be explored for all sorts of other things that may unravel,” said Rinn.
The findings were published in the Nov. 7 issue of the journal Nature Genetics.