In its early weeks, an animal embryo undergoes an incredibly delicate and intricate transformation. Cells grow, divide their genetic material, and separate themselves into brain cells, heart cells, bone cells and all the other parts of the body. But despite centuries of research, we still don’t understand key parts of this process—one of the most complex in the natural world.
University of Chicago scientists, however, have uncovered a new piece of this puzzle by discovering clues about a mysterious but crucial genetic process in mammal cells.
Published in Science on May 5, the results shed light on a previously unknown pathway of genetic regulation, indicating new research directions to understand the fundamental processes of mammalian development—and could suggest avenues of treatments for disease or other biotechnology.
“This should have profound implications for our understanding of mammalian development,” said Chuan He, senior author on the paper and the John T. Wilson Distinguished Service Professor of Chemistry, Biochemistry and Molecular Biology at UChicago.
Clues to chromatin
Scientists have long known that a gene called FTO (short for "Fat mass and obesity associated") is crucial to animal development. Mice and other mammals who don’t have this gene—or have errors in its code—are rarely born and do not survive long. It’s also known to be somehow involved in different human cancers. But no one knew exactly why FTO was so important or how it functioned in the body.
“We knew that it concentrated in brain and heart tissue, and plays important roles in brain and heart development—and that it mostly gathers in the cell nucleus in primary tissues— but not much beyond that, mechanistically,” said He.
A new clue came from an unexpected avenue.
For years, He’s lab has been exploring FTO and its ability to perform a particular process called reversible RNA methylation. This process is a way that cells regulate themselves; it impacts most basic biological processes in mammals. Essentially, cells can place and remove markers on RNA that change the outcome of gene expression. When He and his lab discovered FTO was doing this in 2011, it opened up an entirely new field of research.
Scientists are still cataloguing where and how RNA methylation works in the body, but it’s increasingly apparent that the process plays a major role in the genetics of mammals and perhaps other animals: A 2020 study from He’s lab, for example, hinted at its role in shaping how DNA itself is stored and transcribed.
In the new study, He’s lab uncovers evidence that FTO controls the methylation of RNA pertaining to a certain area of the genome known as LINE elements. That means this methylation regulates the packaging of DNA, or the chromatin state, as well as determining which genes are turned on and off, and when. Such functions would be particularly crucial as an animal grows and develops inside the embryo.
“It looks as though this is indeed a key role of FTO—not the only one, but a major one,” said He.
“LINE elements account for roughly 18% of the human genome and appears something like 1.4 million times. They’re a huge part of our genome.”
If FTO is missing and can’t control LINE elements, cells cannot properly regulate their gene expression—causing catastrophic problems in an animal’s development.
Specifically, the LINE elements FTO works on are retrotransposons, a kind of genetic element sometimes called “jumping genes” because they can move their positions within the genome. These are known to be very important for development, as well as different kinds of diseases.
The discovery may also further related research in He’s group, which showed last year that introducing the FTO gene into plants spurred them to produce significantly longer root systems and yield 50% more crops.
“We still don’t know the exact mechanism by which this works in plants, but this discovery may hint that FTO is acting on retrotransposons in the plant genome, which would be a valuable clue,” said He.
By understanding the mechanism, scientists could hone the process for efficiency and results.
The research was a collaboration with scientists from Tongji University in China.
Citation: “FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development.” Wei et al, Science, May 5, 2022.
Funding: U.S. National Institute of Health, National Key R&D Program of China, National Natural Science Foundation of China, Howard Hughes Medical Institute.