Gutenberg Open Science: Decoding splicing regulatory networks in cancer-relevant genes

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-6712

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DC Field	Value	Language
dc.contributor.author	Cortés López, Mariela	-
dc.date.accessioned	2022-02-08T12:42:10Z	-
dc.date.available	2022-02-08T12:42:10Z	-
dc.date.issued	2022	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/6722	-
dc.description.abstract	Alternative splicing is a highly regulated cellular process, relevant to the generation of protein diversity. Elements in the sequence of the transcripts regulate splicing in cis. These cis-elements are bound by trans-acting factors which, in their majority, are RNA binding proteins (RBPs). The interactions between cis-elements and trans-acting factors define the splicing code. Meanwhile, errors in splicing regulation have been frequently associated with diseases, highlighting the need to understand the mechanisms and consequences of mis-splicing. The first part of this work describes the development of a high throughput mutagenesis assay that allows us to look at the impact of individual mutations in the splicing of the exon 11 in the proto-oncogene RON. This assay uncovered the splicing network of RON exon 11 and identified HNRNPH as a relevant regulator. We also show how HNRNPH cooperatively regulates RON exon 11 splicing in a switch-like manner. During the second part of this work, I present the story of a spurious isoform, known as ex2Δpart. This isoform is an example of an exonic intron (exitron) with suggested potential as a therapeutic marker. We show how ex2Δpart is instead an artefact of reverse transcription (RT). Using bioinformatical analysis, we describe other artefacts (named “falsitrons”). Our work also suggests new strategies to refine isoform annotation. The previous chapters also serve as a precedent for the second high-throughput study presented here: the mutagenesis of CD19 exon 2. CD19 is the target of the CART(Chimeric Antigen Receptor T)-19 therapy, and mis-splicing of its second exon has been associated with therapy resistance. Here, we present a high-throughput mutagenesis assay that characterises the cis- and trans-regulators in the region between exons 1-3 of CD19. The study also provides new information on the regulatory network of splicing of CART-19 relapse patients. Together, the regulatory networks described in this work contribute to interpreting mutations in two cancer-relevant genes. In addition, this work also presents a collection of distinct approaches to improve splicing annotations. The tools and analysis described here can be extended to other important mis-splicing events, helping to decipher the splicing code.	en_GB
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	500 Naturwissenschaften	de_DE
dc.subject.ddc	500 Natural sciences and mathematics	en_GB
dc.title	Decoding splicing regulatory networks in cancer-relevant genes	en_GB
dc.type	Dissertation	de
dc.identifier.urn	urn:nbn:de:hebis:77-openscience-f64315fd-cbda-4761-aa85-bcf70c7213ab8	-
dc.identifier.doi	http://doi.org/10.25358/openscience-6712	-
jgu.type.dinitype	doctoralThesis	en_GB
jgu.type.version	Original work	de
jgu.type.resource	Text	de
jgu.date.accepted	2022-01-19	-
jgu.description.extent	190 Seiten, Diagramme	de
jgu.organisation.department	FB 10 Biologie	de
jgu.organisation.year	2021	-
jgu.organisation.number	7970	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	500	de
jgu.organisation.ror	https://ror.org/023b0x485
Appears in collections:	JGU-Publikationen

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