Snord116 Post-transcriptionally Increases Nhlh2 mRNA Stability: Implications for Human Prader-Willi Syndrome

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dc.contributor.authorKocher, Matthew A.en
dc.contributor.authorHuang, Fenix W.en
dc.contributor.authorLe, Erinen
dc.contributor.authorGood, Deborah J.en
dc.date.accessioned2021-12-14T16:45:59Zen
dc.date.available2021-12-14T16:45:59Zen
dc.date.issued2021-06-15en
dc.date.updated2021-12-14T16:45:57Zen
dc.description.abstractThe smallest genomic region causing Prader-Willi Syndrome (PWS) deletes the non-coding RNA SNORD116 cluster; however, the function of SNORD116 remains a mystery. Previous work in the field revealed the tantalizing possibility that expression of NHLH2, a gene previously implicated in both obesity and hypogonadism, was downregulated in PWS patients and differentiated stem cells. In silico RNA: RNA modeling identified several potential interaction domains between SNORD116 and NHLH2 mRNA. One of these interaction domains was highly conserved in most vertebrate NHLH2 mRNAs examined. A construct containing the Nhlh2 mRNA, including its 3'-UTR, linked to a c-myc tag was transfected into a hypothalamic neuron cell line in the presence and absence of exogenously-expressed Snord116. Nhlh2 mRNA expression was upregulated in the presence of Snord116 dependent on the length and type of 3'UTR used on the construct. Furthermore, use of actinomycin D to stop new transcription in N29/2 cells demonstrated that the upregulation occurred through increased stability of the Nhlh2 mRNA in the 45 minutes immediately following transcription. In silico modeling also revealed that a single nucleotide variant (SNV) in the NHLH2 mRNA could reduce the predicted interaction strength of the NHLH2:SNORD116 diad. Indeed, use of an Nhlh2 mRNA construct containing this SNV significantly reduces the ability of Snord116 to increase Nhlh2 mRNA levels. For the first time, these data identify a motif and mechanism for SNORD116-mediated regulation of NHLH2, clarifying the mechanism by which deletion of the SNORD116 snoRNAs locus leads to PWS phenotypes.en
dc.description.versionAccepted versionen
dc.format.extentPages 1101-1110en
dc.format.extent10 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1093/hmg/ddab103en
dc.identifier.eissn1460-2083en
dc.identifier.issn0964-6906en
dc.identifier.issue12en
dc.identifier.orcidGood, Deborah [0000-0003-0136-0975]en
dc.identifier.other6226238 (PII)en
dc.identifier.pmid33856031en
dc.identifier.urihttp://hdl.handle.net/10919/106983en
dc.identifier.volume30en
dc.language.isoenen
dc.publisherOxford University Pressen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000670925600003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectLife Sciences & Biomedicineen
dc.subjectBiochemistry & Molecular Biologyen
dc.subjectGenetics & Heredityen
dc.subjectLONG NONCODING RNASen
dc.subjectHELIX 2 NHLH2en
dc.subjectSIGNAL TRANSDUCERen
dc.subjectEXPRESSIONen
dc.subjectTARGETSen
dc.subjectOBESITYen
dc.subjectACTINOMYCINen
dc.subjectPREDICTIONen
dc.subjectACTIVATORen
dc.subjectDELETIONen
dc.subject06 Biological Sciencesen
dc.subject11 Medical and Health Sciencesen
dc.subjectGenetics & Heredityen
dc.titleSnord116 Post-transcriptionally Increases Nhlh2 mRNA Stability: Implications for Human Prader-Willi Syndromeen
dc.title.serialHuman Molecular Geneticsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2021-04-01en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Human Nutrition, Foods, & Exerciseen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Durelle Scotten

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