Unique collaborative effort proves value of some “junk” genes

January 21, 2014

From his days in graduate school, through his postdoctoral fellowship, and now as a Harvard Stem Cell scientist, John Rinn, PhD, has been digging through the bulk of the human genome, challenging the prevailing belief that the bulk of the genome is biological “junk.” Ever since the Human Genome Project decoded the genome, the prevailing view has been that only the two percent of the genome making proteins, the building blocks of cells, was important. The rest of the genome was deemed not functional, or “junk.”

But now, Rinn and Harvard Stem Cell Institute colleagues, including neurobiologist Paola Arlotta, PhD, have carried out an elegant and much needed experiment in which they have demonstrated that much of what has been dismissed as functionless “junk” in fact plays as vital a role as the protein-coding genes that make up only two percent of the genome.

Rinn and his colleagues have generated eighteen strains of mutant mice, from each of which a different piece of the ‘junk’ genome, or so-called long intergenic noncoding RNAs (lincRNAs), was removed: If the lincRNA was truly “junk,” nothing should have happened.

What they found was quite the opposite. In fact obvious defects were observed in seven of the eighteen mutant strains—three even died shortly after birth, and there is reason to believe many more also are defective. The authors report these and more findings in the new online journal eLife, initiated by the Howard Hughes Medical Institute, the Wellcome Trust, and the Max Planck Institute.

Martin Sauvageau, Loyal Goff, PhD, and Simona Lodato, the lead authors on the study say it will take years to study all the mice, but a first initial global characterization of the mice determined that seven had obvious defects—they died, they were reduced in size, and had lung and brain defects. And many others, they say, have problems that are more subtle.

“There has been a lot of skepticism whether these long noncoding RNAs are important for living organisms,” said Rinn, “but you can’t say this is junk without testing it. The question will always be what percentage is junk, and what’s functional. But what we need to do is look at lincRNAs with the same careful focus we’ve applied to protein-coding genes, using genetics to characterize them, and see what role they play on a molecular and organismal scale.”

Rinn and Arlotta see their collaboration as at once highly unusual, and at the same time indicative of the way the Department of Stem Cell and Regenerative Biology, in which they are both faculty members, brings together scientists of disparate backgrounds and interests.

“How do a neuroscientist and an RNA biologist come together,” Rinn asked rhetorically. “That’s the story of our department; two scientists coming together to do something neither would have done on their own. And our labs have become seamless. That’s something the department aims for,” he said.

“I’m a geneticist who had never worked with mice; Paola is a neuroscientist who had experience with mice, but for whom this kind of genetic experiment was new—but she has a history of being a classic neurobiologist who takes risky, successful technological leaps. This set of experiments constituted a huge risk for both of us, and for the postdocs who did the work,” Rinn said.

Said Arlotta, “we got into this because we thought these (lincRNA) molecules could be another layer of explanation of how a tissue as complex and mysterious as the brain is made. And indeed we found that these are key molecules for brain development.”

The lincRNAs control the stem cells that give rise to a “particular class of neurons…that are important in the expansion of the brain, in the part that controls intelligent behavior, cognition and perception – the part of the brain that makes us,” Arlotta said.

“When we removed the specific lincRNA we looked at the mouse brain and” the progenitors are reduced, and “as a consequence probably, the population (of neurons) that sits on top of the cerebral cortex are reduced…It’s likely that in the future we’ll see a number of studies showing that other lincRNAs are involved in specific behaviors,” Arlotta said, adding that “the brain likes this junk RNA.”

Photo: This is the team of scientists who appear to have demonstrated that lincRNA, thought by some to be the junk of genes, in fact plays a vital role in development. From the left - Simona Lodato, Loyal Goff, John Rinn, Paola Arlotta, and Marin Sauvageau (Credit: B. D. Colen/Harvard Staff)