Functional characterisation of tissue-specific cis-regulatory modules during zebrafish endoderm organogenesis

这个由MRC资助的博士培训伙伴关系（DTP）将尖端的分子和分析科学与数据分析中的创新计算方法结合在一起，使学生能够解决以假设为主导的生物医学研究问题。这是一个为期4年的计划，其第一年涉及一系列教学模块和两个基于实验室的研究项目，导致跨学科生物医学研究硕士学位。前两个学期包括一系列教学模块，让学生在多学科科学中获得坚实的基础。学生还参加了一系列由学术和行业专家领导的大师班，这些专家在分子，细胞和组织动力学，微生物学和感染，应用生物医学技术以及人工智能和数据科学领域。在第三和夏季学期，学生在他们选择的实验室进行两个为期11周的研究项目。项目：内胚层是脊椎动物胚胎的三个主要胚层之一，对呼吸道和胃肠道以及所有相关器官，如成人的肝脏，胰腺和甲状腺做出了重大贡献。内胚层的先天性缺陷非常普遍。此外，内胚层在发育过程中对其他周围组织的图案化具有关键作用。例如，心脏和颅面发育中的许多先天性缺陷可能是由于内胚层内的基因表达缺陷。人们越来越认识到，发生某些先天性异常的风险可能会受到控制基因表达的基因组区域（称为顺式调节模块（CRM，例如增强子））的遗传变异和突变的影响，而不是蛋白质中的突变。编码序列。因此，了解关键内胚层基因的表达是如何控制的，对于阐明先天性疾病的机制基础和预测其发展的风险至关重要。在这个项目中，学生将利用斑马鱼作为模式生物的许多优势，以确定控制内胚层器官形成过程中基因表达的CRM，以验证CRM子集的功能并测试其突变的影响。这将通过功能基因组学、生物信息学、转基因荧光报告斑马鱼的生产、共聚焦显微镜和图像分析相结合的跨学科方法来实现。因此，该项目提供多种MRC战略技能优先事项的培训。功能基因组学数据的生物信息学分析将需要与定量和跨学科技能主题相一致的方法和技术培训，而研究正常功能和突变影响的转基因动物的生产和成像与整个生物体生理学主题相关。

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.