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RNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome.

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dc.contributor.authorPacheco, Natasha L.en
dc.contributor.authorHeaven, M. R.en
dc.contributor.authorHolt, Leanne M.en
dc.contributor.authorCrossman, D. K.en
dc.contributor.authorBoggio, K. J.en
dc.contributor.authorShaffer, S. A.en
dc.contributor.authorFlint, D. L.en
dc.contributor.authorOlsen, Michelle L.en
dc.coverage.spatialEnglanden
dc.date.accessioned2018-03-09T16:15:30Zen
dc.date.available2018-03-09T16:15:30Zen
dc.date.issued2017en
dc.description.abstractBACKGROUND: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MeCP2. Much of our understanding of MeCP2 function is derived from transcriptomic studies with the general assumption that alterations in the transcriptome correlate with proteomic changes. Advances in mass spectrometry-based proteomics have facilitated recent interest in the examination of global protein expression to better understand the biology between transcriptional and translational regulation. METHODS: We therefore performed the first comprehensive transcriptome-proteome comparison in a RTT mouse model to elucidate RTT pathophysiology, identify potential therapeutic targets, and further our understanding of MeCP2 function. The whole cortex of wild-type and symptomatic RTT male littermates (n = 4 per genotype) were analyzed using RNA-sequencing and data-independent acquisition liquid chromatography tandem mass spectrometry. Ingenuity® Pathway Analysis was used to identify significantly affected pathways in the transcriptomic and proteomic data sets. RESULTS: Our results indicate these two "omics" data sets supplement one another. In addition to confirming previous works regarding mRNA expression inMecp2-deficient animals, the current study identified hundreds of novel protein targets. Several selected protein targets were validated by Western blot analysis. These data indicate RNA metabolism, proteostasis, monoamine metabolism, and cholesterol synthesis are disrupted in the RTT proteome. Hits common to both data sets indicate disrupted cellular metabolism, calcium signaling, protein stability, DNA binding, and cytoskeletal cell structure. Finally, in addition to confirming disrupted pathways and identifying novel hits in neuronal structure and synaptic transmission, our data indicate aberrant myelination, inflammation, and vascular disruption. Intriguingly, there is no evidence of reactive gliosis, but instead, gene, protein, and pathway analysis suggest astrocytic maturation and morphological deficits. CONCLUSIONS: This comparative omics analysis supports previous works indicating widespread CNS dysfunction and may serve as a valuable resource for those interested in cellular dysfunction in RTT.en
dc.description.versionPublished versionen
dc.format.extent56 - ? page(s)en
dc.identifier.doihttps://doi.org/10.1186/s13229-017-0174-4en
dc.identifier.eissn2040-2392en
dc.identifier.orcidOlsen, ML [0000-0003-1394-664X]en
dc.identifier.urihttp://hdl.handle.net/10919/82486en
dc.identifier.volume8en
dc.languageengen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/29090078en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectMulti-cellular deficitsen
dc.subjectProteomeen
dc.subjectRett syndromeen
dc.subjectTranscriptomeen
dc.subjectAnimalsen
dc.subjectCerebral Cortexen
dc.subjectChromatography, High Pressure Liquiden
dc.subjectDisease Models, Animalen
dc.subjectFemaleen
dc.subjectGenotypeen
dc.subjectMaleen
dc.subjectMethyl-CpG-Binding Protein 2en
dc.subjectMiceen
dc.subjectMice, Inbred C57BLen
dc.subjectMice, Knockouten
dc.subjectNeuronsen
dc.subjectPhenotypeen
dc.subjectProteomicsen
dc.subjectRNAen
dc.subjectRett Syndromeen
dc.subjectSequence Analysis, RNAen
dc.subjectTandem Mass Spectrometryen
dc.titleRNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome.en
dc.title.serialMol Autismen
dc.typeArticle - Refereeden
dc.type.otherResearch Support, N.I.H., Extramuralen
dc.type.otherResearch Support, Non-U.S. Gov'ten
dcterms.dateAccepted2017-10-02en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen
pubs.organisational-group/Virginia Tech/Science/School of Neuroscienceen

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