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Investigating upstream regulation of sox32 and its molecular role in endoderm and left-right organiser specification
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Talbot, Conor David (2023) Investigating upstream regulation of sox32 and its molecular role in endoderm and left-right organiser specification. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3984186~S15
Abstract
Sox32 is a transcription factor and master regulator of zebrafish endoderm and correct dorsal forerunner cell (DFC) specification. Absence of sox32 causes a failure in endoderm to develop, and dorsal forerunner cells, the progenitors of the left-right patterning centre, are not functional. Overexpression of sox32 expands endodermal and DFC progenitor gene expression. Despite the importance of sox32, it is unclear how sox32 expression is initiated. T-box factors such as Eomesa act upstream of sox32, but whether other T-box factors function similarly is not known. Eomes function may differ between mammals and fish as mammalian Eomes is required for endoderm specification, unlike zebrafish Eomesa. Additionally, the up and downstream regulation of sox32 is unknown. Nodal signalling is also required for endoderm and left-right patterning, and the extent to which Sox32 relies on Nodal signalling is unknown. This study aimed to establish whether alternative splicing of Eomesa or T-box factors with overlapping expression induce markers of endoderm and DFCs. This study also aimed to profile the binding of Sox32 and investigate the requirement of Nodal for sox32 induced gene expression and chromatin accessibility. Overexpression (OE) of T-box factors in early zebrafish gastrulas, demonstrated mouse Eomes isoforms are functionally similar, and zebrafish Eomesa is partially functionally redundant with T-box factor Tbx16. Furthermore, Eomesa induces DFC marker vgll4l via Sox32. Sox32 binds near sox32 induced genes and accessible chromatin sites. Gene expression and chromatin accessibility were investigated using RNA-seq and ATAC-seq, respectively, in sox32 OE Nodal deficient embryos. Endodermal genes immediately downstream of sox32 were upregulated by Sox32 independently of Nodal, but upstream genes expressed in endoderm and DFC progenitors were downregulated. Genes expressed in endoderm and DFC progenitors with proximal Sox32 binding but reduced chromatin accessibility and expression in sox32 OE Nodal deficient embryos likely represent critical Sox32 Nodal-dependent targets.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QL Zoology | ||||
Library of Congress Subject Headings (LCSH): | Logperch -- Genetics, Logperch -- Embryology, Transcription factors -- Research | ||||
Official Date: | 31 March 2023 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | School of Life Sciences | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Nelson, Andrew | ||||
Sponsors: | Biotechnology and Biological Sciences Research Council (Great Britain) | ||||
Format of File: | |||||
Extent: | 479 pages, 18 pages : illustrations | ||||
Language: | eng |
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