A “coding” long non-coding RNA

from Genetic Engineering News

Although long noncoding RNAs (lncRNAs) are by definition noncoding, they are known to encode disproportionately short molecules—mere polypeptides, not proteins. Whether these polypeptides matter very much is another question. They could represent nothing more than transcriptional noise, or they could be—as a new study suggests—functionally relevant.

In the new study, scientists based at Beth Israel Deaconess Medical Center (BIDMC) computationally predicted and experimentally confirmed the presence of “many” lncRNA-encoded polypeptides that were once “hidden.” More importantly, the scientists demonstrated that at least one of these polypeptides is functionally relevant.

This peptide, a 90-amino-acid-long molecule encoded by the lncRNA LINC00961, is called Small regulatory Polypeptide of Amino acid Response (SPAR). It appears to play an important role in modulating the activity of the mechanistic target of rapamycin complex 1 (mTORC1) protein complex, which is a critical sensor of nutrient availability within cells. The complex also regulates a variety of cellular processes, including translation, metabolism, cell growth, and proliferation; alterations in its function can lead to diseases such as cancer.

The new findings, which appeared December 26 in a paper (“mTORC1 and Muscle Regeneration Are Regulated by the LINC00961-Encoded SPAR Polypeptide”) that appeared in Nature, suggest that lncRNAs are functionally relevant. Specifically, they may help control cellular components in a tissue-specific manner.

“We show that the SPAR-encoding lncRNA is highly expressed in a subset of tissues and use CRISPR/Cas9 engineering to develop a SPAR-polypeptide-specific knockout mouse while maintaining expression of the host lncRNA,” wrote the paper’s authors. “We find that the SPAR-encoding lncRNA is downregulated in skeletal muscle upon acute injury, and using this in vivo model we establish that SPAR downregulation enables efficient activation of mTORC1 and promotes muscle regeneration.”

The BIDMC scientists used computational analyses to predict potential polypeptides that could be encoded by known lncRNA molecules, and then they used mass spectrometry to determine if these putative polypeptides were actually expressed. After uncovering a number of novel polypeptides, they focused on SPAR. This polypeptide, they found, is expressed in a number of tissue types, including muscle.

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Matsumoto A, Pasut A, Matsumoto M, Yamashita R, Fung J, Monteleone E, Saghatelian A, Nakayama KI, Clohessy JG, Pandolfi PP. (2017) mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature 541(7636):228-232. [abstract]

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