Interdisciplinary team discovers new genetic elements of cell reprogramming

An interdisciplinary group of leading Harvard geneticists and stem cell researchers has found a new genetic aspect of cell reprogramming that may ultimately help with the fine-tuning of induced pluripotent stem (iPS) cells into specific cell types.

The researchers identified a set of genetic elements — large intergenic non-coding RNAs, or lincRNAs — never before known to be involved in cellular reprogramming. The scientists, whose study was published online in November by Nature Genetics, have affiliations with HSCI, the Broad Institute of Harvard and Massachusetts Institute of Technology, Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), Children’s Hospital Boston, and Beth Israel Deaconess Medical Center (BIDMC).

“This is the first time that this new type of RNA gene has been implicated in the reprogramming process,” said John Rinn, PhD, a corresponding author of the study who is affiliated with HSCI, SCRB, the Broad Institute, and BIDMC. “It’s important to find as many routes to reprogramming as possible. This finding gives us another set of keys to play on the genomic piano that controls the ‘music’ of cellular reprogramming.

“This is a group of RNAs that comes from the dark region of the genome,” said Rinn. Unlike the RNA messenger molecules that play a key role in the production of proteins, these genes act through their RNA form. “We don’t know everything they do, but they clearly are involved in the reprogramming process.”

“We know reprogramming resets the genome [of the reprogrammed cell] globally,” said George Daley, MD, PhD, of HSCI and Children’s Hospital Boston and, along with Rinn, one of the two senior authors of the Nature Genetics paper. “What we’ve learned by working with John John Rinn, PhD, and Sabine Loewer, PhD, are part of an interdisciplinary group of scientists that discovered a new genetic aspect of cell reprogramming. [Rinn] is that lincRNAs play essential roles in the reprogramming process. We’ve even identified one lincRNA that enhances reprogramming, which is tantalizing evidence that we can make reprogramming more efficient by harnessing lincRNAs.”

The road to this discovery began when Rinn first arrived at Harvard and the Broad Institute in early 2009. He, Broad Institute Director Eric Lander, PhD, and Mitchell Guttman, PhD, who are also authors on the Nature Genetics paper, discovered a group of 5,000 lincRNAs. “We then worked with George [Daley] to figure out their relevance in reprogramming,” Rinn said. These results demonstrate again the value of interdisciplinary collaboration and its power to accelerate fundamental research.