First Thesis Advisor
Huntington’s disease, 3′UTR isoforms, alternative polyadenylation, huntingtin, polyA site sequencing
Huntington’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.
Romo, LS. Alterations in mRNA 3′UTR Isoform Abundance Accompany Gene Expression Changes in Huntington's Disease. (2017). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 916. DOI: 10.13028/M2FT26. https://escholarship.umassmed.edu/gsbs_diss/916
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Available for download on Friday, February 23, 2018