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Synergising single-cell resolution and 4sU labelling boosts inference of transcriptional bursting
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Edwards, David M. (2022) Synergising single-cell resolution and 4sU labelling boosts inference of transcriptional bursting. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3927644
Abstract
Despite the recent rise of RNA-seq datasets combining single-cell (sc) resolution with 4-thiouridine (4sU) labelling, analytical methods exploiting their power to dissect transcriptional bursting are lacking. Presented here is a mathematical model and Bayesian inference implementation to facilitate joint estimation and confidence quantification of the parameters governing transcriptional bursting dynamics on a genome-wide scale. It is demonstrated that, unlike conventional scRNA-seq, 4sU scRNA-seq resolves temporal parameters and furthermore boosts inference of dimensionless parameters via a synergy between single-cell resolution and 4sU labelling. Accounting for various sources of both biological and technical noise, the observed cell-specific transcript turnovers and abundances are naturally integrated, thus reducing the error across all parameters of interest; both dimensionless and temporal. Applying the method to published 4sU scRNA-seq data indicated that large bursts are required for genes with very high expression levels, such as mitochondrial genes. Linking with published ChIP-seq data uncovered otherwise obscured associations between different parameters and histone modifications, agreeing with but advancing upon previously reported results. Evidence is provided for a link between histone modifications and modulation of bursting dynamics through, for example, effects on transcript stability, with these effects being dependent upon the location of the modification throughout the gene. Algorithm performance was validated using simulated datasets with ground truth target parameter values, both with a detailed analysis at a single-gene scale and with a high level analysis at a genomewide scale.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QH Natural history > QH426 Genetics | ||||
Library of Congress Subject Headings (LCSH): | Genetic transcription, RNA -- Synthesis, Genetic regulation, Transcription factors, Histones | ||||
Official Date: | December 2022 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | School of Life Sciences | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Hebenstreit, Daniel, 1977- ; Dyson, Louise | ||||
Sponsors: | Biotechnology and Biological Sciences Research Council (Great Britain) ; Midlands Integrative Biosciences Training Partnership | ||||
Format of File: | |||||
Extent: | 209 pages : illustrations | ||||
Language: | eng |
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