INVESTIGATING THE ROLES OF ZFP322A AND PATZ1 IN ES CELL IDENTITY AND REPROGRAMMING

Ph.DDOCTOR OF PHILOSOPH

Post-transcriptional regulation in the developing embryo

Embryonic development is critically reliant on well-defined spatial and temporal patterns of gene expression. These patterns are often achieved through the regulation of gene expression at the mRNA level. This form of regulation is commonly referred to as post-transcriptional regulation and is frequently mediated by RNA binding proteins (RBPs) and regulatory sequences located in the untranslated regions (UTRs) of the mRNAs. The mechanisms that underlie these post-transcriptional regulation phenomena have been the focus of an increasing level of attention in recent years. However, their specific roles in embryogenesis, and their relative importance to the different processes that take place in the developing embryo, still require further investigation. In this thesis we focused our attention on post-transcriptional regulation mechanisms that operate in the developing zebrafish embryo, and investigated their importance to embryogenesis from two perspectives: the perspective of a post-transcriptional regulator – the Quaking A RBP – and the perspective of a set of regulatory sequences – the fgf8a alternative 3’UTRs. Quaking A belongs to the STAR family of RBPs, which has been implicated in several late developmental processes. Using a loss-of-function approach, we uncovered evidence for two previously undescribed functions for Quaking A, namely, in posterior body shaping and in the establishment of internal organ laterality. Furthermore, in our search for potential mRNA targets of Quaking A we came across the cell adhesion molecule Cadherin 11, which also appears to contribute to the establishment of internal organ laterality. Our investigation of the fgf8a alternative 3’UTRs, revealed that the most abundant 3’UTR for this gene mediates a strong translational repression, when compared to a more sparsely used alternative 3’UTR, which supports a higher translation efficiency. By inducing a shift in the selection efficiency of the associated polyadenylation sites, we observed a temporally and spatially specific impact of fgf8a 3’UTR usage on embryogenesis, in particular at late stages during sensory system development. In addition, we identified a previously undescribed role for Fgf signalling in the initial stages of superficial retinal vascularization. In conclusion, our investigation of Quaking A revealed two previously undescribed roles for this RBP in embryogenesis, thus adding to the current view of STAR proteins, as major regulators of a considerable diversity of developmental processes. In addition, our study of the fgf8a alternative 3’UTRs revealed that within the wide range of developmental processes that involve the fgf8a gene, only a specific subset appears to rely critically on the regulation of the relative abundances of these 3’UTRs. Overall, these findings highlight the importance of addressing post-transcriptional regulation mechanisms to fully understand gene and pathway functions in embryonic development

Oncogene and Cancer

This book describes a course of cancer growth starting from normal cells to cancerous form and the genomic instability, the cancer treatment as well as its prevention in form of the invention of a vaccine. Some diseases are also discussed in detail, such as breast cancer, leucaemia, cervical cancer, and glioma. Understanding cancer through its molecular mechanism is needed to reduce the cancer incidence. How to treat cancer more effectively and the problems like drug resistance and metastasis are very clearly illustrated in this publication as well as some research result that could be used to treat the cancer patients in the very near future. The book was divided into six main sections: 1. HER2 Carcinogenesis: Etiology, Treatment and Prevention; 2. DNA Repair Mechanism and Cancer; 3. New Approach to Cancer Mechanism; 4. New Role of Oncogenes and Tumor Suppressor Genes; 5. Non Coding RNA and Micro RNA in Tumorigenesis; 6. Oncogenes for Transcription Factor