Show simple item record

dc.contributor.authorEwels, Philip
dc.date.accessioned2014-09-03T13:57:33Z
dc.date.available2014-09-03T13:57:33Z
dc.date.issued2013-06-11
dc.identifier.otherPhD.36473
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/245861
dc.description.abstractThe eukaryotic cell nucleus is a highly organised organelle, with distinct specialised sub- compartments responsible for specific nuclear functions. Within the context of this functional framework, the genome is organised, allowing contact between specific genomic regions and sub-compartments. Previous work has shown that genes in both cis and trans can make specific contacts with each other. I hypothesise that such a preferred juxtaposition may impact the propensity for specific cancerinitiating chromosomal translocations to occur. In this thesis, I describe how I have extended and developed a ligation based proximity assay known as enriched 4C. I have coupled this technique with high throughput sequencing to determine genomic regions that spatially co-associate with the proto-oncogenes MLL, ABL1 and BCR. In addition to further developing the laboratory protocol, I have created bioinformatics tools used in the analysis of the sequencing data. I find that the association profiles of the three genes show strong correlation to the binding profile of RNA polymerase II and other active marks, suggesting that transcribed genes have a propensity to associate with other transcribed regions of the genome. Each gene also exhibits a unique repertoire of preferred associations with specific regions of the genome. Significantly, I find that the most frequent trans association of BCR is telomeric chromosome 9, encompassing its recurrent translocation partner gene ABL1. Interestingly, ABL1 is not at the maximum point of interaction. I use DNA-fluorescence in-situ hybridisation to validate the e4C association. My data supports a hypothesis that gene transcription has a direct role on genome organisation. I suggest that preferred co-associations of genes at transcription factories may promote the occurrence of specific chromosomal translocations.en
dc.titleSpatial organisation of proto-oncogenes in human haematopoietic progenitor cellsen
dc.typeThesisen
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridgeen
dc.publisher.departmentBabraham Instituteen
dc.identifier.doi10.17863/CAM.16324
rioxxterms.freetoread.startdate2016-09-03


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record