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Recently, the scientific research team led by Professor He Chuan, a well-known Chinese scientist at the University of Chicago, and Professor Gao Yawei and Professor Gao Shaorong of Tongji University, published a paper in the top academic journal Science, revealing an unknown genetic regulatory pathway in the process of mammalian cell development. Professor He Chuan pointed out: "This discovery will have a profound impact on our understanding of mammalian development. ”
This work focuses on a reversible change that occurs on RNA molecules. RNA, especially messenger RNA (mRNA), is the "intermediary" between DNA and the cell's protein-making process. Translated from RNA to protein, cells use various enzymes to add or remove chemical groups from the RNA. Although these chemical modifications do not affect the molecular sequence of the RNA, they can change the molecular structure, stability, and function of the RNA, and ultimately affect the translation of specific mRNA into proteins, that is, change gene expression.
In mammalian cells, N6-methyladenine (m6A) is the most common and widely modified modification of mRNA. In 2011, Professor He Chuan and his colleagues were the first to discover that FTO (fat mass and obesity-related proteins) played an important role in erasing m6A modifications. FTO is also the first protease known to erase chemical modifications on RNA, a discovery that opens up entirely new areas of RNA epigenetics research.
Image credit: 123RF
A series of studies have shown that although FTO is only closely related to obesity by name (and FTO does affect obesity), this protein is crucial in mammalian development. In particular, animals that play an important role in the development of the two most critical organs, the brain and the heart, lack the FTO gene or have a genetic error, are severely defective and can hardly be born alive.
The researchers speculate that among the various functions in which FTO is involved, the work of performing RNA demethylation may be the most fundamental role of this protein. To confirm this, finding out the main physiological substrates of FTO in the process of organization and development has become a mystery that needs to be solved urgently.
It was in this study that the scientists found key clues. They found that in mouse embryonic stem cells (mESCs), FTO mediated m6A demethylation of the reversed line1 (long interspersed nuclear element-1) RNA.
FTO affects the state of chromatin by mediating m6A demethylation of LINE1 RNA (Image source: Reference[1])
Reversing possums are mediated by RNA, which can be retrotranslated into DNA and can move throughout the genome, sometimes referred to as "jumping genes." LINE is one such genetic component, which is found in large quantities in the human genome, accounting for about 18% of the human genome, and appears nearly 1.4 million times.
The new study found that FTO shapes the local chromatin state by regulating methylation of LINE1 RNA, which in turn affects when genes containing LINE1 elements turn on and when they turn off.
These functions are especially important in animal embryos as they grow and develop. The researchers observed during the development of mouse oocytes and embryos that if the FTO is missing and the LINE element cannot be controlled, the cells cannot properly regulate their gene expression, creating problems early in the animal's development.
The researchers conclude their abstract: "Our results show that FTO has a broad effect on line1 RNA m6A demethylation in mammals." ”
This discovery not only provides a new research path for understanding the basic processes of mammalian development and treating related diseases, but may also open up new directions for other biotechnology fields. For example, Professor He Chuan and his collaborators recently discovered that introducing the Fto gene into crops such as rice stimulates them to produce longer root systems and increase crop yields by 50 percent. "We don't yet know the exact mechanism by which FTO works in plants, but this new finding may suggest that FTO may act on reversed posteriors in plant genomes, which would be a valuable clue." Professor He said.
Dr. Jiangbo Wei and Dr. Xianbin Yu of the University of Chicago, and Dr. Lei Yang and Xuelian Liu of Tongji University are the co-first authors of this article. Professor He Chuan of the University of Chicago, Professor Gao Yawei of Tongji University, and Professor Gao Shaorong of Tongji University are the co-corresponding authors of this article. Professor Li Xuekun of Zhejiang University, Associate Researcher Huang Boxian of Nanjing Medical University and Researcher Liu Jun of Peking University also participated in this work.
Resources:
[1] Jiangbo Wei et al., (2022) FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development. ScienceDoi: 10.1126/science.abe9582
[2] UChicago scientists uncover clues to mysterious but crucial genetic process. Retrieved May 6, 2022 from shttps://news.uchicago.edu/story/uchicago-scientists-uncover-clues-mysterious-crucial-genetic-process
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