Surprise discovery shakes up our understanding of gene expression
A group of scientists at the University of Chicago has discovered a previously unknown way to make our genes a reality.
Rather than following a one-way path from DNA to RNA to proteins, the latest study shows that RNA itself modulates the way DNA is transcribed - using a chemical process that is increasingly evident as vital to biology. This discovery has important implications for our understanding of human disease and drug design.
"It seems to be a fundamental pathway that we didn't know about. Every time it happens, it promises to open up entirely new directions of research and investigation," said Professor Chuan He, a world-renowned chemist.
The human body is one of the most complex machines in existence. Every time you scratch your nose, you're using more complex engineering than any rocket or supercomputer ever designed. It has taken us centuries to deconstruct this mechanism, and every time someone discovers a new mechanism, a few other mysteries of human health come to light - and new treatments become available.
For example, in 2011, he opened a new avenue of research with the discovery of a particular process called reversible RNA methylation, which plays a key role in how genes are expressed.
The image many of us remember of learning in school is one of orderly progression: DNA is transcribed into RNA, which then makes proteins that do the real work of living cells. But it turns out there are a lot of wrinkles.
Her team discovered that molecules called messenger RNAs, previously known as simple messengers that carry instructions from DNA to proteins, actually have their own impact on protein production. This is done through a reversible chemical reaction called methylation; He's main breakthrough was to show that this methylation was reversible. It was not a one-way, one-time transaction; it could be erased and reversed.
"This discovery brought us into a modern era of RNA modification research, which has really exploded in recent years," said He. "This is how much gene expression is critically affected. It affects a wide range of biological processes - learning and memory, circadian rhythms, and even something as fundamental as how a cell differentiates into, for example, a blood cell or a neuron.
His team has also identified and characterized a number of "reader" proteins that recognize methylated mRNA and influence the stability and translation of the target mRNA.
But while his lab was working with mice to understand the mechanisms, they began to see that the methylation of messenger RNA could not fully explain everything they observed.
This was reflected in other experiments. "The data from the community were saying there's something else, something extremely important that we're missing - something that has a critical impact on many early developmental events, as well as human diseases such as cancer," he said.
His team discovered that a group of RNAs called chromosome-associated regulatory RNAs, or carRNAs, use the same methylation process, but these RNAs do not code for proteins and are not directly involved in protein translation. Instead, they controlled the way DNA itself was stored and transcribed.
"This has major implications in fundamental biology," he said. "It directly affects gene transcripts, not just some of them. It could induce a global change in chromatin and affect the transcription of 6,000 genes in the cell line we studied.
He sees major implications in biology, particularly in human health, ranging from identifying the genetic basis of disease to better treatment of patients.
"There are several biotechnology companies actively developing small molecules that inhibit RNA methylation, but at the moment, even if we manage to develop therapies, we don't have a complete mechanical picture of what is happening," he said. "This offers a huge opportunity to help guide the indication of the disease to test inhibitors and to suggest new opportunities for pharmaceuticals".
Their breakthrough is only the beginning, he said. "I think it represents a conceptual shift," he said. "Barriers like these are hard to crack, but once you do, everything flows from there."
