Functional characterisation of tissue-specific cis-regulatory modules during zebrafish endoderm organogenesis
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:
The endoderm, which comprises one of the three primary germ layers of the vertebrate embryo, makes major contributions to the respiratory and gastrointestinal tracts and all associated organs, such as liver, pancreas and thyroid in adults. Congenital defects of the endoderm are highly prevalent. Additionally, the endoderm has key roles in patterning other surrounding tissues during development. For example, many congenital defects in heart and craniofacial development are likely to be due to defective gene expression within the endoderm. There is an increasing realisation that the risk of developing certain congenital abnormalities can be influenced by genetic variants and mutation in regions of the genome that control gene expression, known as cis-regulatory modules (CRMs, e.g. enhancers), rather than mutations in protein coding sequences. Understanding how the expression of key endodermal genes is controlled will therefore be pivotal to elucidating the mechanistic basis for congenital disorders and predicting the risk of their development. In this project the student will exploit the many advantages of zebrafish as a model organism to identify CRMs controlling gene expression during endoderm organogenesis, to characterise the function of a subset of CRMs and test the effects of their mutation. This will be achieved through an interdisciplinary approach combining functional genomics, bioinformatics, production of genetically modified fluorescent reporter zebrafish, confocal microscopy and image analysis. As such, the project provide training in multiple MRC strategic skills priorities. Bioinformatics analysis of functional genomics data will require training in methods and techniques aligned with the themes of Quantitative and Interdisciplinary skills, while the production and imaging of genetically modified animals to study both normal functions and the influence of mutations is relevant to the theme of Whole Organism Physiology.
Project:
The endoderm, which comprises one of the three primary germ layers of the vertebrate embryo, makes major contributions to the respiratory and gastrointestinal tracts and all associated organs, such as liver, pancreas and thyroid in adults. Congenital defects of the endoderm are highly prevalent. Additionally, the endoderm has key roles in patterning other surrounding tissues during development. For example, many congenital defects in heart and craniofacial development are likely to be due to defective gene expression within the endoderm. There is an increasing realisation that the risk of developing certain congenital abnormalities can be influenced by genetic variants and mutation in regions of the genome that control gene expression, known as cis-regulatory modules (CRMs, e.g. enhancers), rather than mutations in protein coding sequences. Understanding how the expression of key endodermal genes is controlled will therefore be pivotal to elucidating the mechanistic basis for congenital disorders and predicting the risk of their development. In this project the student will exploit the many advantages of zebrafish as a model organism to identify CRMs controlling gene expression during endoderm organogenesis, to characterise the function of a subset of CRMs and test the effects of their mutation. This will be achieved through an interdisciplinary approach combining functional genomics, bioinformatics, production of genetically modified fluorescent reporter zebrafish, confocal microscopy and image analysis. As such, the project provide training in multiple MRC strategic skills priorities. Bioinformatics analysis of functional genomics data will require training in methods and techniques aligned with the themes of Quantitative and Interdisciplinary skills, while the production and imaging of genetically modified animals to study both normal functions and the influence of mutations is relevant to the theme of Whole Organism Physiology.
