New Form of Gene Regulation Hints at Hidden Dimension of DNA

New Form of Gene Regulation
Hints at Hidden Dimension of DNA

This discovery that pseudogenes may indeed have a function could transform biology, says Pier Paolo Pandolfi, a cancer geneticist and biologist at Beth Israel Deaconess Medical Center in Boston and Harvard Medical School who led the study. The finding has already altered the perspectives of people in his lab, he says. “Now we are unable to think the same. It changes the way we do biology on a daily basis.”

"This means that not only have we discovered a new language for mRNA, but we have also translated the previously unknown language of up to 17,000 pseudogenes and at least 10,000 long non-coding (lnc) RNAs. Consequently, we now know the function of an estimated 30,000 new entities, offering a novel dimension by which cellular and tumor biology can be regulated, and effectively doubling the size of the functional genome."

Pseudogenes are considered to be defunct relatives of known genes. But there is some surprising news: pseudogenes are functional and could have a role in the control of cancer. Two experts discuss the significance of these findings for understanding the regulation of gene expression and cancer biology.

An entire class of seemingly useless genetic components may actually regulate gene activity, suggests a study that — though preliminary — has potentially transformative implications for biology. The findings involve apparently redundant copies of genes, called “pseudogenes,” and RNA molecules that would normally carry out genetic instructions, but appear to be disabled. When it comes to altering the activity of PTEN, a cancer tumor-regulating gene, these components are neither redundant nor broken. Instead they help turn PTEN on and off. The same might happen for thousands of other genes. If so, the findings have revealed an entire new class of operators in the programming language of life. “This is a completely new way by which genes can be regulated. It’s something that up to this point has been undiscovered,” said Leonardo Salmena, a Harvard Medical School geneticist and co-author of the study, published June 23 in Nature. The implicit question is whether the process is unique to PTEN and its decoys, or applies to the human genome’s other 19,000 pseudogenes. If so, the junk may actually be vitally important to development and disease. “There’s a huge domain of non-coding RNAs. Until now, we couldn’t make sense of them,” said study co-author Pier Paolo Pandolfi, also a Harvard Medical School geneticist. “Now we have a way to understand them. We’re not in the dark.” Indeed, each human genome has many pseudogenes, or near-perfect copies of functional genes. These pseudogenes produce RNA that doesn’t seem to do anything, but simply floats in cellular space. Scientists have long assumed pseudogenes and their RNA to be so much cruft, the biological equivalent of leftover code that’s yet to be excised from a program. But the researchers in this study, whose specialty is a tumor-suppressing gene called PTEN, noticed that RNA produced by PTEN’s pseudogenes was shaped exactly like the real thing. According to Pandolfi, if the findings truly represent a widespread new class of RNA, they will double the known number of functional genetic elements. “This brings into play thousands of RNAs that we previously had no idea what they did,” said Salmena. “We think we’ve only hit the tip of the iceberg with this phenomena.” “To what extent this is going to be a general mechanism, the onus is now on the scientific community to begin looking in other systems,” said Singer. “I presume they will.”