Alternative polyadenylation at Mest
department or school: Medicine, Faculty of
department or school: Medical Genetics, Department of
data provider: DSpace
degree campus: UBCV
creator: Ashworth, Nolan
issued: 2024-11-18T23:10:36Z
issued: 2024
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Imprinting, an epigenetic phenomenon where only one allele of a gene is expressed depending on its parental origin, plays a significant role in mammalian development. The sub-proximal MMU6 imprinting domain, particularly, includes the paternally expressed gene Mest and the maternally expressed genes Copg2 and Klf14. In addition to the mature mRNA, Mest has a much longer isoform produced via alternative polyadenylation, termed MestXL. Mest is a candidate gene for the growth restriction Silver-Russell syndrome (SRS), since maternal uniparental disomy for the chromosomal region containing MEST (mUPD7) has been identified in 5-10% of SRS patients and because Mest knockout mice exhibit a growth restriction phenotype. The tissue-specific switch from Mest to MestXL formation seems to be linked to differential expression of the downstream gene Copg2. Copg2, which is adjacent and antisense to Mest/MestXL, is normally biallelically expressed. However, in tissues where MestXL is produced, such as the developing central nervous system, Copg2 shows preferential maternal expression, suggesting a potential regulatory role for MestXL in this process since it is exclusively expressed form the paternal allele. This thesis explores the expression and regulation of MestXL, which induces secondary imprinting of Copg2 within the central nervous system (CNS). Although it is known that MestXL is expressed in the CNS, the specific cell types, mechanisms behind its production and effect on paternal Copg2 expression remain unclear. I leveraged RNA-seq data and established an ESC-derived cortical neuron differentiation protocol to investigate MestXL expression. To study the sufficiency of the Mest mRNA polyA signal (PAS) in MestXL production in cortical neurons, I also developed a double-fluorescent Mest primary PAS transgenic ESC line. Finally, I constructed an endogenous MestXL reporter-truncation vector, for eventual integration at Copg2 and forward genetics studies of factors involved in M…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/89674
note: ALTERNATIVE POLYADENYLATION AT MEST by Nolan Ashworth B.Sc., University of Alberta, 2020 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in The Faculty of Graduate and Postdoctoral Studies (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) November 2024 © Nolan Ashworth, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled: Alternative Polyadenylation at Mest submitted by Nolan Ashworth in partial fulfilment of the requirements for the degree of Master of Science in Medical Genetics Examining Committee: Louis Lefebvre, Associate Professor, Medical Genetics, UBC Supervisor Carolyn Brown, Professor, Medical Genetics, UBC Supervisory Committee Member Michael Underhill, Professor, Cellular & Physiological Sciences and School of Biomedical Engineering, UBC Supervisory Committee Member Catherine Van Raamsdonk, Associate Professor, Medical Genetics, UBC Additional Examiner iii Abstract Imprinting, an epigenetic phenomenon where only one allele of a gene is expressed depending on its parental origin, plays a significant role in mammalian development. The sub-proximal MMU6 imprinting domain, particularly, includes the paternally expressed gene Mest and the maternally expressed genes Copg2 and Klf14. In addition to the mature mRNA, Mest has a much longer isoform produced via alternative polyadenylation, termed MestXL. Mest is a candidate gene for the growth restriction Silver-Russell syndrome (SRS), since maternal uniparental disomy for the chromosomal region containing MEST (mUPD7) has been identified in 5-10% of SRS patients and because Mest knockout mice exhibit a growth restriction phenotype. The tissue-specific switch from Mest to MestXL formation seems to be linked to differential expression of the downstream gene Copg2. Copg2, which is adjacent and antisense to Mest/MestXL, is normally biallelic…
has type: Thesis/Dissertation
date issued: 2025-05
is shown at: 10.14288/1.0447285
language: eng
degree discipline: Medical Genetics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Lefebvre, Louis
type: Text
identifier URI: http://hdl.handle.net/2429/89674