Embryonic stem cells can follow one of two main routes. They can either differentiate, becoming cells of a specific lineage such as blood cells or neurons, or they can stay in a pluripotent state, duplicating themselves without losing the ability to become any cell in the body. When the researchers turned off each lincRNA in turn, they found dozens that suppress genes that are important only in specific kinds of cells. They also found dozens of lincRNAs that cause the stem cells to exit the pluripotent state.
"It's a balancing act," said Guttman. "To maintain the pluripotent state, you need to repress differentiation genes."
The researchers also uncovered a critical clue about how lincRNAs carry out their important job. Through biochemical analysis, they found that lincRNAs physically interact with key proteins involved in influencing cell fate to coordinate their responses.
"The lincRNAs appear to play an organizing role, acting as a scaffold to assemble a diverse group of proteins into functional units," said John Rinn, an author on the paper, an assistant professor at Harvard University and Medical School, and a senior associate member of the Broad Institute. "lincRNAs are like team captains, bringing together the right players to get a job done."
"By understanding how these interactions form, we may be able to engineer these RNAs to do what we want them to do," said Guttman. "This could make it possible to target key genes that are improperly regulated in disease."
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