Researchers at Columbia University Irving Medical Center have identified thousands of molecules—produced by the genome’s “junk” DNA—that are found only in human fat cells and play an important role in how we store and use fat. The finding, published in Science Translational Medicine, could lead to better treatments for obesity and other metabolic disorders.
Knowing that humans and mice share many of the same genes, previous studies of fat regulation have relied on studies of mice. But few discoveries made in mice have been successfully translated into therapies for human metabolic disorders.
That may be because humans and mice are not as genetically similar as we thought. Although the two species share 92 percent of their protein-making genes, the vast majority of the genome does not code for proteins. Researchers in the past had mostly dismissed this portion of the genome as “junk” DNA with no discernible purpose.
“But more and more evidence suggests that it’s not junk at all, and parts of it are very different between humans and mice,” says Muredach Reilly, MBBCh, MSCE, director of the Irving Institute for Clinical and Translational Research at Columbia University Irving Medical Center and Florence and Herbert Irving Endowed Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons. “It raises the question: Are these parts of the genome, not found in mice, doing something in people?”
Hundreds of lincRNA molecules found in human fat cells do not exist in mice
To see if “junk” DNA plays a different role in human fat cells than in mice fat cells, Reilly’s team focused on a large portion of the genome that creates molecules called long intergenic non-coding RNAs, or lincRNAs, which evolved rapidly and are very different between mice and humans. LincRNAs were only discovered within the past decade, but it’s now known there are likely tens of thousands of them in humans.
More and more, it’s looking like lincRNAs are part of the reason why we are different from mice and other animals and they may be unique contributors to human disease.
Using unusually thorough techniques to detect RNA molecules, Reilly’s team analyzed fat tissue from 25 healthy, lean participants. Their analysis identified more than 4,000 different lincRNAs, of which 85 percent are not found in mice. Of these, 1,001 molecules were shared among all of the participants.
Not all lincRNAs have a function, but the researchers found signs that many of the lincRNAs unique to humans had features that suggest they also may contribute to fat regulation. The researchers took a close look at the most abundant one—linc-ADAL, which is not found in mice and had never been studied before—and found that it plays a significant role in how fat cells develop and how they store fat.
The team also discovered subsets of lincRNAs that were expressed differently in males and females and others that were expressed differently in people who had undergone bariatric surgery. These characteristics suggest potential roles for these lincRNAs in observed sex differences in fat storage as well as in obesity and its complications.
New techniques needed to understand human lincRNAs
But because mice don’t have the same lincRNAs as humans, new and more sophisticated model systems are needed to translate these findings into knowledge of diseases in humans and more effective therapies for metabolic diseases.
“We need more creative approaches to move forward, such as using human organoids [miniature lab-grown tissue structures that mimic many of the characteristics of actual organs], mouse models that are engineered to incorporate human DNA or can reconstitute human tissues and organs, and advanced human genetics and bioinformatics that can help to implicate roles for specific lincRNAs in human disease,” Reilly says. These approaches are both technically challenging and more expensive to implement than traditional mouse model approaches.
Emerging studies have found that human-specific lincRNAs are abundant in all tissues, as well as in tumors, potentially opening a wholly new approach to the study of disease and development of new therapies. Each of these tissues has its own set of lincRNAs, which will certainly complicate research and drug development because each tissue will need to be studied individually. “But this heterogeneity is also a good thing,” Reilly says. “Because lincRNAs are tissue-specific, drugs that target lincRNAs found in one type of tissue are unlikely to affect other tissues.”
What was once considered junk DNA may hold exciting new keys to the development of effective therapies for metabolic diseases.
“Most scientists have ignored lincRNAs that differ between humans and mice,” he adds. “The very large number of potentially functional human lincRNAs not found in mice goes against the longstanding belief that if a part of the genome isn’t conserved across species—from fruit flies to mice to humans—it is probably not important.
“But more and more, it’s looking like lincRNAs are part of the reason why we are different from mice and other animals and they may be unique contributors to human diseases as well as human characteristics. And what was once considered junk DNA may well hold exciting new keys to the development of effective therapies for metabolic diseases.”
The paper is titled “Interrogation of non-conserved long intergenic noncoding RNAs in human adipose identifies a regulatory role of linc-ADAL in adipocyte metabolism.”
Muredach Reilly is also associate dean for clinical and translational research at Columbia University.
Other authors: Xuan Zhang (Columbia University Irving Medical Center), Chenyi Xue (CUIMC), Jennie Lin (Northwestern University), Jane F. Ferguson (Vanderbilt University), Amber Weiner (University of Pennsylvania), Wen Liu (CUIMC), Yumiao Han (University of Pennsylvania), Christine Hinkle (University of Pennsylvania), Wnjun Li (University of Pennsylvania), Hongfeng Jiang (Beijing Anzhen Hospital and Beijing Institue of Heart, Lung, and Blood Vessel Disease), Sager Gosai (University of Pennsylvania), Melanie Hachet (CUIMC), Benjamin A. Garcia (University of Pennsylvania), Brian D. Gregory (University of Pennsylvania), Raymond E. Soccio (University of Pennsylvania), John B. Hogenesch (Cincinnati Children’s Hospital Medical Center), Patrick Seale (University of Pennsylvania), and Mingyao Li (University of Pennsylvania).
The research was supported by grants from the National Institutes of Health (R01 HL113147, K24 HL107643, R01 HL111694, R01 GM108600, R01 GM110174, R01 AI118891, R01 HL122993) and the American Diabetes Association (1-16-PDF-137).
The authors declare that they have no competing interests.