Genomic regulation of vertebrate development

Lead Research Organisation: University of Exeter
Department Name: Mathematics

Abstract

What is this project about?
Our DNA is a collection of instructions for how a living being functions and develops. All the cells in our body have the same DNA sequence, but not all the cells are the same. For example, a brain cell has a very different structure, appearance and function to a skin or heart cell. So what makes the cells different?
The way the DNA is used by the cells is similar to how a musician reads a music sheet; the DNA is like the sequence of musical notes. However, in a music sheet there are also instructions for the dynamics and rhythm of the music. In a similar way, there are mechanisms that decide which parts of the DNA are used by the cell; these are broadly called the epigenome of a cell. During early stages of development of a new organism, the epigenome is very important in determining the cell type of each cell in the adult organism.
In this project I will identify changes in these mechanisms in different cell types across the early development of a new organism.
Why is this important?
The early development of a new human is a very vulnerable process. Errors during this time can increase the risk of someone developing a disease later in life. This includes mental health diseases such as schizophrenia. Researchers have been studying the mechanisms that regulate human development for a long time. However, to this day no one has described the epigenome of the different cell types during early stages of development. As a consequence, we still do not completely understand how the different cell types are generated and how errors during this process result in diseases.
My project will help us to:
1) Understand how humans develop;
2) Determine how our different organs are generated;
3) Identify regions of the genome that can be used in the treatment of certain diseases, such as schizophrenia;
4) Understand how the different cell types are determined;
5) Identify regions of the genome that are more vulnerable during early development.
How will I do this?
During early stages of development, the new developing organism is called an embryo. Studying human embryos is a complicated process, which is limited by ethical restrictions. To study human development researchers often rely on animal models that have similarities with humans. In this project I will use zebrafish embryos.
An obvious limitation of using zebrafish is that fish are not humans. However, the zebrafish embryo is surprisingly similar to other animals in the same group (vertebrates), such as mice or humans. In addition, the zebrafish DNA sequence is around 70% similar to humans. The zebrafish embryos develop outside of the mothers' bodies and are transparent. This characteristic makes it easy to see what happens to the embryos during development. Zebrafish are also cheap and easy to keep as an animal model. We can grow a large number of embryos in a very short time.
Firstly, I will extract different cell types from zebrafish embryos at different stages of early development. I will then extract the DNA from these cells and use advanced laboratory methods to read the epigenome of these cells. To generate results, I will use powerful computer programs and software.
To identify regions of the DNA that can be used in the treatment of mental health diseases, I will partner with the pharmaceutical company Eli Lilly. I will compare DNA regions that are very important in development with regions that are involved in mental health disorders. The DNA regions in common to both processes can be investigated as targets for new medication. Eli Lily experts will teach me the best methods to generate the results of this project. In return, these results will inform them of possible drug targets for these diseases.
By the end of this project we will have a greater insight into the mechanisms that regulate human development. We will identify target regions that can be used to create new medication for mental health diseases.

Technical Summary

PROJECT AIM: This project will identify the genomic regions that play a crucial role during early vertebrate development and which of these are potential pharmaceutical targets for neurological disorders.
BACKGROUND: Epigenetic and gene expression changes during development play crucial roles in determining cell fate. Insults during this time can cause abnormalities in these mechanisms and lead to diseases later in life, such as schizophrenia or ADHD. Determining the genomic regions that undergo changes during early development is essential to understand the molecular mechanisms involved in development and developmental disorders. To this date, no study has identified the genome-wide epigenetic and gene expression changes that occur in different cell types across several stages of early development.
APPROACH: I will characterize the regulatory changes in specific cell populations during early development and identify potential targets for pharmaceutical therapies for neurodevelopmental disorders. Firstly, I will isolate purified cell populations from different tissue structures of the zebrafish embryo at different stages of development. These will be isolated using dissection and aspiration and/or cell sorting technologies. I will then characterise dynamic changes in histone modifications, DNA modifications, open chromatin and gene expression in each of these cell populations, using different genome-wide sequencing methods. To analyse these data I will use statistical methods and bioinformatics analyses. Finally, the epigenomic and transcriptomic changes involved in development identified during my fellowship will be compared to the existing genomics and transcriptomic datasets at Eli Lilly (in collaboration with the Lieber Institute for Brain Development and the Psychiatric Genomics Consortium) to help identify potential pharmaceutical targets for neuropsychiatric disorders with developmental origins.

Publications

10 25 50
 
Description Genetics Society Training Grant
Amount £1,000 (GBP)
Organisation The Genetics Society 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 10/2018
 
Description Research-led Initiative Award
Amount £1,000 (GBP)
Organisation University of Exeter 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 07/2019
 
Description Scholarship to attend the Zebrafish Development and Genetics course 2018
Amount $3,290 (USD)
Organisation Marine Biological Laboratory 
Sector Academic/University
Country United States
Start 08/2018 
End 08/2018
 
Description Travel Bursary
Amount £200 (GBP)
Organisation Wellcome Genome Campus 
Sector Private
Country United Kingdom
Start 10/2018 
End 11/2018
 
Description Travel Grant
Amount £400 (GBP)
Organisation Guarantors of Brain 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 10/2018
 
Description Christian Mosimann's lab 
Organisation University of Colorado Denver
Country United States 
Sector Academic/University 
PI Contribution I have spent 2 weeks in Christian's lab to learn a lot of techniques important for my fellowship project.
Collaborator Contribution I have spent 2 weeks in Christian's lab to learn a lot of techniques important for my fellowship project.
Impact No outputs have materialised yet
Start Year 2018
 
Description Talk to year 12 and 13 students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact I gave two talks to students from year 12 and 13 from the Maths School in Exeter about my research and my career progression. This included a Q&A session.
Year(s) Of Engagement Activity 2019