This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: For decades, scientists have understood that each of the roughly 20,000 genes in the human body carries instructions for a single kind of protein. Now, researchers at Harvard Medical School have discovered that instructions from different genes—even those on different chromosomes—can combine to create chimeric mRNAs that produce previously unknown, functional proteins.
The findings, published in Nature, reveal the existence of potentially thousands of new chimeric proteins and demonstrate that at least some play important roles throughout the body. "Nobody knows these exist. Medicine doesn't know they exist, the pharmaceutical industry doesn't know they exist," said senior author Ruaidhrí Jackson, assistant professor of immunology in the Blavatnik Institute at HMS.
"We've discovered an entirely new gene regulation system that could expand the known genome and proteome dramatically." While the researchers don't yet know how widespread the phenomenon is, chimeric proteins could be involved in a variety of systems and may contribute to disease processes that are poorly understood. This overlooked aspect of biology could offer new insights into challenging diseases and provide a new avenue for finding drug targets to treat them. "There are suddenly many new possibilities for the kind of molecules and proteins that cells can create," said Harry Kane, co-first author and HMS and Gene Lay Institute research fellow in immunology in the Jackson Lab.
"If it is possible to leverage chimeric RNAs for drug discovery and medicine, then this is very exciting." While some single-celled and invertebrate organisms, such as trypanosomes and nematodes, can combine genes for regulatory purposes, these systems don't seem to create proteins and have not been found in mammals. The best-known examples of chimeric mRNA in humans came from cancer-causing abnormalities in which DNA breaks into pieces and some of the scattered genes fuse together. RNA sequencing results occasionally suggested that chimeric mRNAs could exist in healthy tissue, but traditional sequencing techniques had difficulty finding them and may have even created some artificially.
"This project was high-risk, high-reward from the very beginning," said co-first author Olivia Venezia, a Harvard Kenneth C. Griffin Graduate School of Arts and Sciences Ph.D. student in immunology in the Jackson Lab. "We didn't know how many chimeric mRNAs we would find or if they would be biologically relevant." Using a new technology called direct RNA sequencing, the researchers were able to compile a list of more than 30,000 chimeric mRNAs that have been observed at least once in mammalian cells—the "dark genome" library, Jackson calls it.
So far, they have been able to profile how almost 400 of these are regulated by inflammatory signals, including chimeric mRNAs conserved in both human and mouse immune cells. The team found that healthy chromosomes can loop together in mouse cells as part of the immune response, bringing normally distant genes into proximity. The newly adjacent genes are transcribed into a chimeric mRNA, which takes part of its sequence from each gene and produces a protein that is a hybrid of the two.
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