Analysis of SOX1 regulation in stem cell and cancerous cell lines

Ahmad, Azaz (2017) Analysis of SOX1 regulation in stem cell and cancerous cell lines. PhD thesis, University of Nottingham.

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Abstract

The SOX family of transcription factors are well-known regulators of diverse cellular events during development. SOX1, which belongs to the SOXB1 sub-family, is a key regulator of neural stem cell fate and a known specific marker of the neuroectoderm lineage. SOX1 plays an important role in early embryonic and postnatal CNS development. Recently, several studies have implicated SOX1 as a tumour suppressor gene in different cancer types. Conversely, SOX1 has also been reported to act as an oncogene in a prostate cancer model. In order to better understand SOX1 gene regulation, this project set out to gain a deeper insight into the regulation of SOX1 in the context of stem cells and cancer, and to identify potential regulatory mechanisms that can significantly regulate its function.

Initially, SOX1 gene expression and its promoter DNA methylation pattern was analysed in a range of cancer cell lines to establish whether SOX1 epigenetic silencing was consistently found in cancer lines. Differential SOX1 expression across the analysed cancer cell lines suggests differential regulation of SOX1 in cancer, accompanied by cancer type dependent epigenetic silencing of SOX1 by DNA methylation.

The second part of the study focused on the characterisation of the structure and expression of a newly identified SOX1 overlapping transcript (SOX1-OT), using RT-PCR and 5’5’RACE techniques. The SOX1-OT genomic locus was found evolutionary conserved across different species. SOX1-OT expression was further analysed in a human neuroprogenitor cell line across different time points of neural differentiation, highlighting its possible role in neural differentiation. Furthermore, the SOX1-OT gene expression profile was matched with SOX1 gene expression in a panel of different stem cell and cancerous cell lines. The co-expression profiles of SOX1-OT and SOX1 in stem cells and carcinogenesis indicated towards a potential role of SOX1-OT regulating SOX1 gene expression.

Finally, a comprehensive bioinformatics analysis was performed to investigate evidence of SOX1 post translational modifications (PTMs). In silico prediction of phosphorylation, acetylation and sumoylation sites support SOX1 PTMs. The predicted PTMs within different SOX1 protein domains may affect its function through altering its DNA binding activities, cellular localisation and interaction with partner proteins.

In conclusion, SOX1 expression in different stem and cancer cell lines is likely to be regulated by promoter DNA methylation, a long non coding RNA (SOX1-OT) and its function by different types of PTMs. These regulatory features may in the future advance the understanding of the SOX1 transcription regulatory network in stem cell developmental processes and its role in cancer development.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Sottile, V.
Tufarelli, C.
Keywords: SOX1, Stem cell, lncRNA, PTMs, SOX1 overlapping transcript, Expression pattern, Transcript variants, Carcinogenesis
Subjects: QS-QZ Preclinical sciences (NLM Classification) > QU Biochemistry
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 41635
Depositing User: Ahmad, Azaz
Date Deposited: 24 Oct 2017 13:45
Last Modified: 26 Oct 2017 04:03
URI: http://eprints.nottingham.ac.uk/id/eprint/41635

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