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CELL BIOLOGY
Lengthy RNAs earn respect as cellular players
R
1072
rators from the Lieber Institute for Brain Development in Baltimore, Maryland, he determined the sequences of all the RNA in preserved brain samples from 307 people. Among the thousands of lncRNAs that Ponting’s team found in each person’s brain tissue—many of them never identified before—about 18% show up in just one individual. Those molecules may be just randomly transcribed and of no utility, Haerty reported at the meeting. But 2728 different lncRNAs were found in more than half the samples, and 251 were expressed in every individual. Their gene sequences overlapped with chemical markers indicative of active transcription—another hint that they are functional. For Ponting, the question now is not so much whether lncRNAs matter as how many of them matter. Rinn also offered new evidence of lncRNA functionality at the meeting. He and Harvard graduate student Moran Cabili, together with Arjun Raj from the University of Pennsylvania and Aviv Regev from the Broad Institute, have developed a way to visualize lncRNAs in single cells from different human tissues. For each lncRNA examined, they add to the cell a fluorescent-tagged probe matching the lncRNA’s sequence. The technique indicated that the distribution of many lncRNAs is not random— which Rinn argues would happen if these molecules were mere garbage. Instead, some lncRNAs are confined to the nucleus, whereas others reside only in the cytoplasm. As more lncRNAs and cells are tested, Rinn hopes to reveal whether “jackpot” cells— cells with anomalously large numbers of lncRNAs—exist. Some have suggested that jackpot cells would indicate that lncRNAs are the product of aberrant transcription in just a few cells. Several researchers at the meeting still think lncRNAs may be minor players in biology. One who did not want to be quoted declared that no graduate student should invest time in them. “I don’t like the hype,” agrees Emmanouil Dermitzakis, a genomicist at the University of Geneva Medical School in Switzerland. “I don’t think we should spend more money on it.” But others see progress. “We now know for sure they are not just garbage,” says Mitchell Guttman, an lncRNA researcher at the California Institute of Technology in Pasadena. “But what they are doing and how they are working, we don’t know.” ■ sciencemag.org SCIENCE
6 JUNE 2014 • VOL 344 ISSUE 6188
Published by AAAS
PHOTO: EZGI HACISULEYMAN/ARJUN RAJ/JOHN RINN
Researchers could envision multiple ways in which lncRNA could act, influencing gene activity by helping regulatory proNA is a virtuoso molecule. What was teins attach to DNA or by binding to the once seen as just a cellular messenger double helix themselves, for example. But takes multiple forms with surprising biological samples typically contained just talents: It can be an enzyme, a dea small number of any specific lncRNA, fense against infection, a gene regulastoking doubts about their functionality. tor, and much more. Now, biologists Chris Ponting, a genomicist at the Uniare debating whether an unusually lengthy versity of Oxford in the United Kingdom, form of RNA is a regular player in the cell or, also reported that their sequences were not more often, a distraction. well conserved across species—as would Surveys of cells have uncovered many be expected if most were vital to survival. thousands of RNA strands 200 bases or more For him and others, that finding cemented long, called long non-coding RNA (lncRNA), their doubts. and several groups have linked specific lncRinn, a longtime supporter of lncRNAs, RNAs to development, cancer, pain, and intried to settle the debate at the end of last flammation. But others suggest they could year. In a study published on 31 December be genomic trash, the spurious byproducts 2013 in eLife, he and colleagues described of gene transcription. the effects of disabling At the Biology of Gegenes for 18 lncRNAs nomes meeting held in mice. They had here last month, sevcarefully examined the eral talks offered eviknown lncRNAs for dence that chasing those that did not these molecules isn’t a overlap with any fool’s errand. With the protein-coding genes discovery that some and selected 18 to lncRNAs are identical eliminate. Three of the in many different tisknockout mice did not sues, and that a few are survive to adulthood; essential to the survival two others had growth of mice, the scientific defects. “If you take community “has gone them out in mice, bad from questions about things happen,” Rinn whether they are relsays. evant at all to how are Ponting, among oththey relevant,” declared ers, was not convinced, one lncRNA speaker, because knocking out John Rinn, a molecuthe lncRNA genes lar biologist at Harvard might also disrupt emUniversity. A new method for visualizing lncRNAs shows bedded regulatory DNA Almost 25 years ago, copies of one (pink) in cell nuclei (blue). that might control distwo lncRNAs made tant protein-coding headlines: H19, which plays a role in cancer genes. “A lot of genomic real estate was and in fetal growth, and Xist, which helps taken away,” he says. shut down the second X chromosome in feThe tide may now be turning in favor of males to ensure the proper dosage of gene lncRNAs, however. At the meeting, Philippe activity. Those lncRNAs were considered unBatut of Cold Spring Harbor Laboratory reusual until 2005, when a large-scale project ported comparing five fruit fly species that called FANTOM suggested there were 35,000 had diverged as much as 25 million years ncRNAs, exceeding the number of proteinago. He found that more than 1000 lnccoding genes. These findings created “a big RNAs have been conserved among all the buzz,” says Adam Siepel, a computational bispecies—unlikely if the molecules have no ologist at Cornell University. “Whatever [rebiological role. searchers] were interested in, they wanted to Ponting has also begun to come around. see what lncRNAs had to do with it.” With Oxford’s Wilfried Haerty and collaboBy Elizabeth Pennisi, Cold Spring Harbor, New York
Downloaded from www.sciencemag.org on June 6, 2014
A few of these molecules are clearly important, but just how many?
CELL BIOLOGY
Lengthy RNAs earn respect as cellular players
R
1072
rators from the Lieber Institute for Brain Development in Baltimore, Maryland, he determined the sequences of all the RNA in preserved brain samples from 307 people. Among the thousands of lncRNAs that Ponting’s team found in each person’s brain tissue—many of them never identified before—about 18% show up in just one individual. Those molecules may be just randomly transcribed and of no utility, Haerty reported at the meeting. But 2728 different lncRNAs were found in more than half the samples, and 251 were expressed in every individual. Their gene sequences overlapped with chemical markers indicative of active transcription—another hint that they are functional. For Ponting, the question now is not so much whether lncRNAs matter as how many of them matter. Rinn also offered new evidence of lncRNA functionality at the meeting. He and Harvard graduate student Moran Cabili, together with Arjun Raj from the University of Pennsylvania and Aviv Regev from the Broad Institute, have developed a way to visualize lncRNAs in single cells from different human tissues. For each lncRNA examined, they add to the cell a fluorescent-tagged probe matching the lncRNA’s sequence. The technique indicated that the distribution of many lncRNAs is not random— which Rinn argues would happen if these molecules were mere garbage. Instead, some lncRNAs are confined to the nucleus, whereas others reside only in the cytoplasm. As more lncRNAs and cells are tested, Rinn hopes to reveal whether “jackpot” cells— cells with anomalously large numbers of lncRNAs—exist. Some have suggested that jackpot cells would indicate that lncRNAs are the product of aberrant transcription in just a few cells. Several researchers at the meeting still think lncRNAs may be minor players in biology. One who did not want to be quoted declared that no graduate student should invest time in them. “I don’t like the hype,” agrees Emmanouil Dermitzakis, a genomicist at the University of Geneva Medical School in Switzerland. “I don’t think we should spend more money on it.” But others see progress. “We now know for sure they are not just garbage,” says Mitchell Guttman, an lncRNA researcher at the California Institute of Technology in Pasadena. “But what they are doing and how they are working, we don’t know.” ■ sciencemag.org SCIENCE
6 JUNE 2014 • VOL 344 ISSUE 6188
Published by AAAS
PHOTO: EZGI HACISULEYMAN/ARJUN RAJ/JOHN RINN
Researchers could envision multiple ways in which lncRNA could act, influencing gene activity by helping regulatory proNA is a virtuoso molecule. What was teins attach to DNA or by binding to the once seen as just a cellular messenger double helix themselves, for example. But takes multiple forms with surprising biological samples typically contained just talents: It can be an enzyme, a dea small number of any specific lncRNA, fense against infection, a gene regulastoking doubts about their functionality. tor, and much more. Now, biologists Chris Ponting, a genomicist at the Uniare debating whether an unusually lengthy versity of Oxford in the United Kingdom, form of RNA is a regular player in the cell or, also reported that their sequences were not more often, a distraction. well conserved across species—as would Surveys of cells have uncovered many be expected if most were vital to survival. thousands of RNA strands 200 bases or more For him and others, that finding cemented long, called long non-coding RNA (lncRNA), their doubts. and several groups have linked specific lncRinn, a longtime supporter of lncRNAs, RNAs to development, cancer, pain, and intried to settle the debate at the end of last flammation. But others suggest they could year. In a study published on 31 December be genomic trash, the spurious byproducts 2013 in eLife, he and colleagues described of gene transcription. the effects of disabling At the Biology of Gegenes for 18 lncRNAs nomes meeting held in mice. They had here last month, sevcarefully examined the eral talks offered eviknown lncRNAs for dence that chasing those that did not these molecules isn’t a overlap with any fool’s errand. With the protein-coding genes discovery that some and selected 18 to lncRNAs are identical eliminate. Three of the in many different tisknockout mice did not sues, and that a few are survive to adulthood; essential to the survival two others had growth of mice, the scientific defects. “If you take community “has gone them out in mice, bad from questions about things happen,” Rinn whether they are relsays. evant at all to how are Ponting, among oththey relevant,” declared ers, was not convinced, one lncRNA speaker, because knocking out John Rinn, a molecuthe lncRNA genes lar biologist at Harvard might also disrupt emUniversity. A new method for visualizing lncRNAs shows bedded regulatory DNA Almost 25 years ago, copies of one (pink) in cell nuclei (blue). that might control distwo lncRNAs made tant protein-coding headlines: H19, which plays a role in cancer genes. “A lot of genomic real estate was and in fetal growth, and Xist, which helps taken away,” he says. shut down the second X chromosome in feThe tide may now be turning in favor of males to ensure the proper dosage of gene lncRNAs, however. At the meeting, Philippe activity. Those lncRNAs were considered unBatut of Cold Spring Harbor Laboratory reusual until 2005, when a large-scale project ported comparing five fruit fly species that called FANTOM suggested there were 35,000 had diverged as much as 25 million years ncRNAs, exceeding the number of proteinago. He found that more than 1000 lnccoding genes. These findings created “a big RNAs have been conserved among all the buzz,” says Adam Siepel, a computational bispecies—unlikely if the molecules have no ologist at Cornell University. “Whatever [rebiological role. searchers] were interested in, they wanted to Ponting has also begun to come around. see what lncRNAs had to do with it.” With Oxford’s Wilfried Haerty and collaboBy Elizabeth Pennisi, Cold Spring Harbor, New York
Downloaded from www.sciencemag.org on June 6, 2014
A few of these molecules are clearly important, but just how many?
