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Controlling gene activity in human development

Research reveals long non-coding RNA is important in regulating cell processes. This discovery may lead to insights which improve muscle regeneration and cancer treatments.

Scientific research over the past decade has concentrated almost exclusively on the 2 percent of the genome's protein coding regions, virtually ignoring the other 98 percent, a vast universe of non-coding genetic material previously dismissed as nothing more than 'junk.'

Now, a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) reveals that one type — called long non-coding RNA(lncRNA) — may be critically important for controlling tissue-specific cellular components. Published online December 26 in the journal Nature, the new research points to lncRNA's key role in helping control processes related to muscle regeneration and cancer.

Long non-coding RNAs appear to be transcribed from our DNA in a similar manner to messenger RNAs — but are not translated into proteins.

While lncRNA molecules do not produce lengthy proteins, researchers wondered whether some may contain segments of sequences that can code for very short proteins, or polypeptides.

Investigators used computational analyses to predict which potential polypeptides could be encoded by known lncRNA molecules. They then used mass spectrometry to determine if these assumed polypeptides are actually functioning.

"With this approach we actually identified many expressed [working] hidden polypeptides and went on to characterize one in particular,"
Pandolfi explained. This specific lncRNA molecule is now called LINC00961 and encodes a 90 amino acid polypeptide.

"Whether such small, hidden polypeptides are actually functional, or represent 'translational noise' within the cell is still relatively unclear. Our team set about trying to understand to what extent lncRNA molecules might actually encode functional polypeptides, and how important such peptides might be."

Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA, and senior author.

A variety of molecular and biochemical experiments revealed that the LINC00961 polypeptide plays an important role in the activity of the mTORC1 protein complex — which is a critical sensor of the available nutrients within a cell. The mTORC1 protein complex also regulates a variety of cell processes: translation, metabolism, cell growth, and proliferation.

Alterations in the mTORC1 protein complex function can lead to diseases such as cancer.

Because the LINC00961 polypeptide appears to specifically block mTORC1's ability to sense stimulation by amino acids, investigators named the peptide the lncRNA SPAR (or Small regulatory Polypeptide of Amino acid Response).

Pandolfi and his team found that SPAR encoded lncRNA is highly functional in a number of tissue types, including muscle.

Experiments conducted in mice demonstrate that through its effects on mTORC1, the SPAR polypeptide helps regulate muscle's ability to regenerate and repair after injury.

Specifically, expression of LINC00961 is blocked following muscle injury in mice, leading to reduced levels of SPAR — but maximum mTORC1 activity, promoting tissue regeneration.

"The experimental approach we used allowed us to eliminate expression of the SPAR polypeptide, while maintaining expression of the host lncRNA," said lead author Akinobu Matsumoto, PhD, research fellow at the Cancer Center at BIDMC and lead author of the study. "We are able to ascribe this function to the coding function of the lncRNA rather than any non-coding function it may also have."

The findings suggest that therapeutic strategies that restrict expression of SPAR in injured muscle may promote a more rapid regeneration of tissue.

The results suggest that lncRNAs may have diverse roles and functions.

Although they may not code for large proteins, lncRNAs may produce small polypeptides that can fine tune the activity of critical cell components.

These findings expand the repertoire of peptide-coding genes in the human genome that should be studied and annotated. The study also provides insight on how mTORC1 may be attuned to meet the needs of specific tissues.

"An ability to target such modulators could be of great advantage from a therapeutic perspective, allowing for control of mTORC1 activity in cells or tissues that express such modulators while not affecting its activity and function in other tissue and cell types."

John Clohessy, PhD, Instructor in Medicine, BIDMC, a senior member of Pandolfi's research team and co-author.

Indeed, a key feature of many lncRNAs is that their function is often highly tissue-specific. Targeting small polypeptides encoded by lncRNA molecules may provide the key to regulating common cell components in a tissue-specific manner.

Because the mTORC1 complex is frequently deregulated in conditions such as cancer, the research team is now looking to see if SPAR can influence cell functions of mTORC1 that might be involved in different diseases.

"We are very excited about this discovery. It represents a new and startling mechanism by which important sensory pathways can be regulated within cells, and we believe it will have important implications for how we approach the design of therapies and treatments in the future."

Pier Paolo Pandolfi, MD, PhD

Although long non-coding RNAs (lncRNAs) are non-protein-coding transcripts by definition, recent studies have shown that a fraction of putative small open reading frames within lncRNAs are translated1, 2, 3. However, the biological significance of these hidden polypeptides is still unclear. Here we identify and functionally characterize a novel polypeptide encoded by the lncRNA LINC00961. This polypeptide is conserved between human and mouse, is localized to the late endosome/lysosome and interacts with the lysosomal v-ATPase to negatively regulate mTORC1 activation. This regulation of mTORC1 is specific to activation of mTORC1 by amino acid stimulation, rather than by growth factors. Hence, we termed this polypeptide ‘small regulatory polypeptide of amino acid response’ (SPAR). 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. 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. Our data provide a mechanism by which mTORC1 activation may be finely regulated in a tissue-specific manner in response to injury, and a paradigm by which lncRNAs encoding small polypeptides can modulate general biological pathways and processes to facilitate tissue-specific requirements, consistent with their restricted and highly regulated expression profile.

Study coauthors include BIDMC investigators Akinobu Matsumoto, Alessandra Pasut, Jacqueline Fung, Emanuele Monteleone, and John G. Clohessy. Other co-investigators include Masaki Matsumoto and Keiichi I. Nakayama of Kyushu University, Riu Yamashita of Tohoku University, and Alan Saghatelian of the Salk Institute for Biological Studies.

This work was supported in part by the National Institutes of Health grants R01 CA082328 and R35 CA197529.

About Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding.

BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www.bidmc.org.
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Dec 28, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Key roles for long non-coding RNAs (lncRNAs) in
the regulation of gene function have begun to emerge.
Image Credit: Nature Review



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