SACM - United Kingdom
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Item Restricted The role of isoform switching and neoantigen formation in the response to radiation(University of Oxford, 2023) Abdulghani, Majd Yousef; Humphrey, Timothy CarterThis thesis investigates the role of isoform switching in response to ionising radiation (IR) and the modulation of this process by SRSF1, a proto-oncogenic splicing factor. Utilising deep RNA-sequencing of B-cell lines from ten healthy individuals, the study reveals extensive IR-induced isoform switching across the transcriptome, leading to potentially shorter transcripts that influence DNA damage response, apoptosis, and cell cycle arrest. Intriguingly, nearly half of the genes exhibiting isoform-level changes showed no differential expression at the gene level, highlighting the importance of isoform-specific analysis in understanding cellular responses to IR. The RNA-binding protein SRSF1 is identified as a mediator of IR-induced isoform switching. Loss of SRSF1 expression, which is a common response to IR across various cell types, enhances radiosensitivity in cell lines and in cancer patients. Moreover, the thesis explores the combined effect of SRSF1 knockdown and IR on triple-negative breast cancer cells, revealing an altered antigenic landscape with 86 putative neoantigens, and therefore offering insights into novel targeted immunotherapies. The findings propose SRSF1 as a prognostic marker for radiotherapy efficacy in the short-term, and present a foundation for future therapeutic approaches targeting SRSF1 in cancer treatment.10 0Item Restricted The role of Inversin in left-right patterning and cardiac development(Newcastle University, 2024-04-30) Alaradi, Mashael; Henderson, DeborahVertebrate bodies have left-right (L-R) asymmetry, an arrangement set up early in development. L-R patterning is thought to be initiated by symmetry-breaking events at the embryonic node, which contains motile cilia that generate an asymmetric fluid flow to define the left-side of the embryo. This process results in normal organ positioning known as situs solitus (SS), where the gall bladder and most of the liver are on the right, whereas the spleen, stomach, pancreas and heart reside on the left. Disruption to L-R patterning can result in a spectrum of laterality defects, ranging from situs inversus totalis (SI, complete mirror imagery) or heterotaxy where organ positioning is randomised across the L-R axis of the body. In particular, the heart, a highly asymmetric organ, appears very sensitive to improper L-R patterning, with strong links between heterotaxy and Congenital Heart Defects (CHDs). In humans, laterality disturbances have been reported in several diseases which impact cilia structure and function such as Kartaganer syndrome and Primary Cilia Dyskinesia, whilst large scale mutagenesis screens in mice have supported a link between ciliopathies, heterotaxy and CHDs. The Inversin (Invs) mouse mutant, Inv, was initially identified due to complete penetrance of SI. Subsequently, Invs has been shown to localise to cilia and is also suggested to function as a molecular switch between different Wnt signalling pathways. There is also some evidence demonstrating that loss of Invs in mice results in CHDs. However, the direct link between laterality disturbances and CHDs in Inv mutants remains unknown, given the possibility that loss of Invs may alter Wnt signalling, which is required for normal heart development. Therefore, this project sought to establish whether Invs has a laterality-independent role in heart development, or if its role in LR patterning is responsible for CHDs. Firstly, I investigated the spatial and temporal distribution of Invs in the mouse heart, showing that the expression pattern of Invs is dynamic during cardiac development. I then examined Inv mouse mutants for laterality defects at embryonic and fetal stages. This analysis revealed that although SI was common, many Inv mutants did not have body axis inversion although they did have laterality disturbance including right isomerism, left isomerism and situs solitus; CHDs were observed in all Inv mutants examined. Analysis of the CHD observed suggested similarities with mouse mutants with improper addition of a migratory population of cardiac progenitor cells, known as the Second Heart Field (SHF). Accordingly, to examine a laterality independent role for Invs in the heart, I analysed the SHF in Inv mutant embryos and showed that abnormalities in this cell population could not be accounted for simply on the basis of a disruption in L-R patterning. Finally, as it has been proposed that Invs acts as a switch molecule between Wnt pathways, I investigated whether there could be a genetic interaction affecting L-R patterning and heart development between Invs and Vangl2, a non-canonical Wnt (PCP) component in. These data suggested a complex interaction between these two genes. Together, my work supports the idea that Invs could plays laterality-independent roles in heart development. However, significant further work is necessary in order to confirm this exciting finding.47 0