More than a century ago, hardy individuals dropped everything to search for Klondike gold. Today, a new breed of adventurers is changing course to search for a different kind of gold: information at a scale so tiny, it couldn’t be read until recently. It’s called “non-genetic information.”
Biochemists are as excited as prospectors without having to haul packs up remote snowbanks. More secrets of the cell are coming to light, revealing new levels of regulation in the burgeoning field of epigenetics. In Nature, Cassandra Willyard expresses the fervor that is growing in labs around the world: “An epigenetics gold rush: new controls for gene expression.” As she reports on “How rediscovered chemical tags on DNA and RNA are shaking up the field,” she uses the word excited or exciting five times. It began in 2008, she explains:
At the time, biologists were getting excited about the epigenome — the broad array of chemical marks that decorate DNA and its protein scaffold. These marks act like a chemical notation, telling the cell which genes to express and which to keep silent. As such, the epigenome helps to explain how cells with identical DNA can develop into the multitude of specialized types that make up different tissues. The marks help cells in the heart, for example, maintain their identity and not turn into neurons or fat cells. Misplaced epigenetic marks are often found in cancerous cells. [Emphasis added.]
What’s new is the assignment of RNA tags to the glossary of non-genetic information. Geneticists were familiar with methyl tags on DNA and histone proteins (the “histone code“), but only recently were these tags recognized as functional elements on the bases of RNA as well. In January, we shared one of those discoveries: a tag named m6a that affects the stability of messenger RNA (mRNA). The number and position of tags on the mRNA affect its lifetime, and consequently its activity. Jaffrey’s team considered this “dynamic and reversible epitranscriptomic mark” an instance of “epitranscriptomic information that determines the fate of mRNA.”
Willyard now has more examples to share. Dr. Chuan He, a chemist at the National Institutes of Health, and his colleague Chao Pan at the University of Chicago set out to look for “chemical notation” on RNA molecules. When they started working together in 2009, He and Pan knew of about 100 chemical tags on RNA, but “nobody knew what they did.” How often are major discoveries made by expecting function? Look what has happened with that focus:
Nine years later, such research has given birth to an ‘ome of its own, the epitranscriptome. He and others have shown that a methyl group attached to adenine, one of the four bases in RNA, has crucial roles in cell differentiation, and may contribute to cancer, obesity and more. In 2015, He’s lab and two other teams uncovered the same chemical mark on adenine bases in DNA (methyl marks had previously been found only on cytosine), suggesting that the epigenome may be even richer than previously imagined. Research has taken off. “I think we’re approaching a golden age of epigenomics and epitranscriptomics,” says Christopher Mason, a geneticist at Weill Cornell Medical College in New York City. “We can actually start to see all these modifications that we knew have been there for decades.”
Their experience mirrors the downfall of the junk DNA myth. Non-coding DNA had been known for many years, but only when researchers intentionally looked for function did the golden age come. Now a new vein of gold is being found in long-ignored RNA tags (some of them known since 1974), but it required breaking out of old dogmas.
The governing rule of molecular biology — the central dogma — holds that information flows from DNA to messenger RNA to protein. Many scientists therefore viewed mRNA as little more than a courier, carrying the genetic information encoded in a cell’s nucleus to the protein factories in the cytoplasm. That’s one reason why few researchers paid much attention to the modifications made to mRNA.
Some of the delay is excusable. Scientists didn’t have the tools we have now for “powerful mass spectrometry and high-throughput sequencing techniques,” Willyard explains. Even with those tools, the work remains difficult. We can only wonder, though, if ‘gold fever’ might have accelerated the development of the tools.
In about 2010, the reversible m6a mark was discovered. “To He, it seemed like proof of an RNA-based system of gene regulation.” The hidden gold veins started to shine under the flashlights. Further studies “revealed more than 12,000 methylated sites on mRNAs, originating from 7,000 genes.”
The maps showed that the distribution of m6A is not random. Its location suggested that the mark might have a role in alternative splicing of RNA transcripts, a mechanism that allows cells to produce multiple versions of a protein from a single gene.
Since then, researchers have uncovered the molecular machines controlling the tags. “Each requires a writer to place it, an eraser to remove it and a reader to interpret it,” Willyard says; “As the identities of these proteins emerged, scientists have come to understand that m6A affects not only RNA splicing, but also translation and RNA stability.” They started finding function all over the place.
This change in mRNA content, which He calls a transcriptome switch, requires precision and careful timing. He thinks that the methyl marks might be a way for cells to synchronize the activity of thousands of transcripts.
By now, labs from Tel Aviv to Boston to Pasadena had gold fever. Researchers wanted to learn how different tissues tag their RNAs, and how the marks differ between organisms from algae to humans. Why, for instance, were some of these marks easier to find in bacteria than mammals? Earlier researchers had walked right past the gold veins.
In 2013, He’s postdoc Fu had found an intriguing paper from the 1970s, which showed that algal DNA contains methylated adenine. “Nobody ever knew the function, and nobody ever followed up,” Fu says.
Fu and a colleague started looking for these marks in algae, and found it in more than 14,000 genes. “And the distribution wasn’t random,” Willyard points out. It clustered near start sites for transcription. The postdocs reasoned that the mark “might be promoting gene activation.” And so it was. Then they discovered that the marks are present in higher animals, too, but at low levels. Catch the fever:
Greer’s lab head, Yang Shi, knew that He had uncovered 6mA in algae, and asked him for help. When He heard what Shi had found, he was excited. “We decided we’re going to do this together,” He says. A couple of months later, He met a researcher in China who had found 6mA in the fruit fly Drosophila. “I almost fell to the floor,” He says. In April 2015, the three papers came out simultaneously in Cell.
Andrew Xiao, who studies epigenetics at Yale University in New Haven, Connecticut, read the articles with interest. Xiao and his colleagues had identified 6mA in mammalian cells, but they hadn’t published their results. “Literally we thought nobody will take interest in this field,” Xiao says. The Cell articles proved him wrong. “We realized we should hurry up.”
And thus it goes. Marks are found to appear, surge, then disappear, indicating they act like a “molecular switch” during development. “His paper was absolutely a bombshell,” one researcher exclaimed, reacting to clear evidence that a certain tag is functional. Another calls the work “incredibly exciting.” Willyard continues the gold rush metaphor in a section, “Mining for more marks.” They’re talking like excited miners looking into their gold pans.
“We are only in the beginning of the story,” Rechavi says. And as the techniques improve, scientists will be able to see these marks more clearly. The wealth of research possibilities makes Mason feel “euphoric“, he says. “It’s like the most exciting time to be working in the field.”
Sound familiar? Vestigial organs must be leftovers of evolution; wait: they have a function! Noncoding DNA strands must be leftovers of evolution: wait, they have a function! These useless tags on RNA, “nobody knew the function, and nobody ever followed up.” Wait! There’s gold in them thar hills!
For an encore, look at this article from the National Institute of Standards and Technology (NIST), “Start codons in DNA and RNA may be more numerous than previously thought.” It’s a bad-news, good-news story about the fall of another dogma. This one is about so-called “start codons” at the beginnings of genes. “It was previously thought that only seven of the 64 possible triplet codons trigger protein synthesis.” But then, to their surprise, Stanford and NIST researchers found that some genes were being expressed without start codons.
To the best of their knowledge, no one had ever systematically explored whether translation could be initiated from all 64 codons. No one had ever proved that you cannot start translation from any codon.
“We kind of all collectively asked ourselves: had anyone ever looked?” said Hecht. A further review of available literature on the topic indicated that the answer was no….
The implications of the work could be quite profound for our understanding of biology.
“We want to know everything going on inside cells so that we can fully understand life at a molecular scale and have a better chance of partnering with biology to flourish together,” said Stanford professor and JIMB colleague and advisor, Drew Endy. “We thought we knew the rules, but it turns out there’s a whole other level we need to learn about. The grammar of DNA might be even more sophisticated than we imagined.”
Needless to say, this discovery opens up additional vistas of information and control in the genome. Also, needless to say, these articles are strangely silent about Darwinian evolution.
Advocates of intelligent design should be pleased but unsurprised by these discoveries. And not to push the gold rush analogy too far, but we note that back in the day, many prospectors who set out for their journey to Alaska and the Klondike did so by way of Seattle. They equipped themselves and embarked just blocks away from what are today Discovery Institute’s offices.
We’re not saying, “We told you so” (although we did). Instead, let’s all capitalize on the excitement of this gold rush. Isn’t the search for function more rewarding than tossing unknown phenomena to the junk pile? ID is delightedly to point the way for the gold rushers to likely veins, with the modest reminder, Knowing how minds create hierarchical levels of information, you can expect to find functions similar to those in computer networks — only even more sophisticated.
Photo: Klondike prospectors, Chilkoot Pass, 1898, by Cantwell, George G. [Public domain], via Wikimedia Commons.