m1A occurs in GC-rich sequence contexts and in genes with structured 5′ UTRs.
Discovery brings RNA to the fore of epigenetics. A new study finds that RNA, DNA template for protein translation, often appears with an extra letter – and this letter is the regulatory key for control of gene expression. The discovery offers insight into different RNA functions in cellular processes and contributions to the development of disease.
“Epigenetics, the regulation of gene expression beyond the primary information encoded by DNA, was thought until recently to be mediated by modifications of proteins and DNA,” said Prof. Gidi Rechavi. “The new findings bring RNA to a central position in epigenetics.”
The number of modified nucleotides (letters) in RNA is 10X larger than that of the letters found in DNA. But what accounts for the evolutionary drive for a large RNA alphabet? RNA molecules have a wide variety of functions, including storage of genetic information as well as catalytic, structural, and regulatory activities. This is in contrast to the important but one-dimensional function of DNA in encoding genetic information. “The 140 or so different modifications that decorate RNA increase significantly the vocabulary of RNA and enable the various types of RNA, including mRNA, rRNA, tRNA, siRNA, miRNA and, lncRNA, to implement their versatile activities,” said Prof. Rechavi.
Prof. Rechavi’s group began exploring modifications of mRNA 4 years ago through addition of a methyl group in position 6 of Adenosine (m6A) in mRNA. The research team then showed that this modification is specific to unique regions of the mRNA molecules and that the modification can be “read” by specific proteins. They also showed that this modification is dynamic and responds to environmental stimuli.
These findings complemented identification by Prof. He’s Uni of Chicago group at the time of an enzyme (FTO) that removes the m6A marks from mRNA. The demonstration of a reversible process that decorates mRNA and affects its stability, translatability, splicing, and localization established a new field of RNA “epigenetics” known as “epitranscriptomics.”
In their new study, they unraveled a new dynamic modification of mRNA – methylation of position 1 of Adenosine (m1A). This modification was shown to be localized in a telltale position near the start of protein translation and linked to increased protein synthesis. Thousands of genes are decorated by this modification, allowing cells to regulate the expression of proteins needed for key biological processes. “We expect disruption of this new regulatory mechanism to be associated with disease states such as cancer and neurodegenerative disorders,” said Prof. Rechavi.
The research groups are currently studying the cellular processes involved in “writing” and “erasing” m1A, as well as the biochemical pathways regulated by this new RNA modification. In the future, they plan to explore the role of m1A methylation in embryonic development and its involvement in cancer and neurodegenerative disorders. https://www.aftau.org/weblog-medicine–health?=&storyid4704=2254&ncs4704=3
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