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dc.contributor.advisorNeil Aronin
dc.contributor.authorRomo, Lindsay S.
dc.date2022-08-11T08:08:46.000
dc.date.accessioned2022-08-23T16:07:41Z
dc.date.available2022-08-23T16:07:41Z
dc.date.issued2017-07-10
dc.date.submitted2017-08-24
dc.identifier.doi10.13028/M2FT26
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32297
dc.description.abstractHuntington’s disease is a neurodegenerative disorder caused by expansion of the CAG repeat in huntingtin exon 1. Early studies demonstrated the huntingtin gene is transcribed into two 3′UTR isoforms in normal human tissue. Decades later, researchers identified a truncated huntingtin mRNA isoform in disease but not control human brain. We speculated the amount of huntingtin 3′UTR isoforms might also vary between control and Huntington’s disease brains. We provide evidence that the abundance of huntingtin 3′UTR isoforms, including a novel mid-3′UTR isoform, differs between patient and control neural stem cells, fibroblasts, motor cortex, and cerebellum. Both alleles of huntingtin contribute to isoform changes. We show huntingtin 3′UTR isoforms are metabolized differently. The long and mid isoforms have shorter half-lives, shorter polyA tails, and more microRNA and RNA binding protein sites than the short isoform. 3′UTR Isoform changes are not limited to huntingtin. Isoforms from 11% of genes change abundance in Huntington’s motor cortex. Only 17% of genes with isoform alterations are differentially expressed in disease tissue. However, gene ontology analysis suggests they share common pathways with differentially expressed genes. We demonstrate knockdown of the RNA binding protein CNOT6 in control fibroblasts results in huntingtin isoform changes similar to those in disease fibroblasts. This study further characterizes Huntington’s disease molecular pathology and suggests RNA binding protein expression may influence mRNA isoform expression in the Huntington’s disease brain.
dc.language.isoen_US
dc.rightsLicensed under a Creative Commons license
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectHuntington’s disease
dc.subject3′UTR isoforms
dc.subjectalternative polyadenylation
dc.subjecthuntingtin
dc.subjectpolyA site sequencing
dc.subjectMolecular and Cellular Neuroscience
dc.titleAlterations in mRNA 3′UTR Isoform Abundance Accompany Gene Expression Changes in Huntington's Disease
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1921&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/916
dc.legacy.embargo2018-02-23T00:00:00-08:00
dc.identifier.contextkey10656842
refterms.dateFOA2022-08-30T15:30:47Z
html.description.abstract<p>Huntington’s disease is a neurodegenerative disorder caused by expansion of the CAG repeat in huntingtin exon 1. Early studies demonstrated the huntingtin<em> </em>gene is transcribed into two 3′UTR isoforms in normal human tissue. Decades later, researchers identified a truncated huntingtin mRNA isoform in disease but not control human brain. We speculated the amount of huntingtin 3′UTR isoforms might also vary between control and Huntington’s disease brains.</p> <p>We provide evidence that the abundance of huntingtin 3′UTR isoforms, including a novel mid-3′UTR isoform, differs between patient and control neural stem cells, fibroblasts, motor cortex, and cerebellum. Both alleles of huntingtin contribute to isoform changes. We show huntingtin 3′UTR isoforms are metabolized differently. The long and mid isoforms have shorter half-lives, shorter polyA tails, and more microRNA and RNA binding protein sites than the short isoform.</p> <p>3′UTR Isoform changes are not limited to huntingtin. Isoforms from 11% of genes change abundance in Huntington’s motor cortex. Only 17% of genes with isoform alterations are differentially expressed in disease tissue. However, gene ontology analysis suggests they share common pathways with differentially expressed genes. We demonstrate knockdown of the RNA binding protein CNOT6 in control fibroblasts results in huntingtin isoform changes similar to those in disease fibroblasts. This study further characterizes Huntington’s disease molecular pathology and suggests RNA binding protein expression may influence mRNA isoform expression in the Huntington’s disease brain.</p>
dc.identifier.submissionpathgsbs_diss/916
dc.contributor.departmentCell Biology
dc.description.thesisprogramMD/PhD
dc.identifier.orcid0000-0003-3407-1168


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