Investigating RNA regulation during embryonic and germline development in zebrafish
Lead Research Organisation:
University of Warwick
Department Name: Warwick Medical School
Abstract
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.
Project:
In early embryos of many animals, maternally provided RNAs and proteins control the earliest developmental processes. This includes the distribution, stability and activity of RNAs involved in cell fate specification events. How RNA molecules are targeted to specific sub-cellular and embryonic regions and how their activity is regulated is not fully understood. For instance, how the germ plasm, a specialised complex of RNAs and proteins essential for germline and sexual development, is stabilised and distributed in early embryos is not understood. The sequence, structure and, more recently, modification of RNAs (such as m6A) has been shown to regulate their localisation and activity. A small set of proteins that recognise the modifications and modulate the RNAs have also been identified, but their mechanisms and functions are not fully understood.
Recent studies have reported a number of m6A-related diseases in humans, including cancer and metabolic disorders, such as obesity. Therefore, it is vital we understand precisely the roles of this modification in development and homeostasis. This project aims to study the role of RNA modifications and the proteins that recognise them during early embryonic development in zebrafish focussing on a known m6A reader, Igf2bp3. Zebrafish is an ideal model organism to study these processes as there are functionally equivalent early development factors in humans and zebrafish, and many fundamental mechanisms are conserved. Igf2bp3 has recently been shown to be important for early embryonic and germline development (Vong et al., 2021).
Using RNA-sequencing the project aims to understand the molecular basis of defects in igf2bp3 mutants. The role of specific candidate RNAs will be addressed using genome editing using CRISPR/Cas9, transcriptome-wide gene expression changes and phenotype analysis. Through the project, the student will adopt an interdisciplinary approach that combines embryology, bioinformatics, genome engineering and in vivo imaging and gain skills training in quantitative and interdisciplinary skills, healthy ageing through the lifecourse and whole organism physiology.
Project:
In early embryos of many animals, maternally provided RNAs and proteins control the earliest developmental processes. This includes the distribution, stability and activity of RNAs involved in cell fate specification events. How RNA molecules are targeted to specific sub-cellular and embryonic regions and how their activity is regulated is not fully understood. For instance, how the germ plasm, a specialised complex of RNAs and proteins essential for germline and sexual development, is stabilised and distributed in early embryos is not understood. The sequence, structure and, more recently, modification of RNAs (such as m6A) has been shown to regulate their localisation and activity. A small set of proteins that recognise the modifications and modulate the RNAs have also been identified, but their mechanisms and functions are not fully understood.
Recent studies have reported a number of m6A-related diseases in humans, including cancer and metabolic disorders, such as obesity. Therefore, it is vital we understand precisely the roles of this modification in development and homeostasis. This project aims to study the role of RNA modifications and the proteins that recognise them during early embryonic development in zebrafish focussing on a known m6A reader, Igf2bp3. Zebrafish is an ideal model organism to study these processes as there are functionally equivalent early development factors in humans and zebrafish, and many fundamental mechanisms are conserved. Igf2bp3 has recently been shown to be important for early embryonic and germline development (Vong et al., 2021).
Using RNA-sequencing the project aims to understand the molecular basis of defects in igf2bp3 mutants. The role of specific candidate RNAs will be addressed using genome editing using CRISPR/Cas9, transcriptome-wide gene expression changes and phenotype analysis. Through the project, the student will adopt an interdisciplinary approach that combines embryology, bioinformatics, genome engineering and in vivo imaging and gain skills training in quantitative and interdisciplinary skills, healthy ageing through the lifecourse and whole organism physiology.
