How to assemble the cardiovascular system: instructions from the genome

Lead Research Organisation: University of Manchester
Department Name: School of Medical Sciences

Abstract

Cardiovascular disease is the leading cause of death worldwide. Inherited DNA sequence variants play a role in conferring risk for disease. Our knowledge of the genetic loci associated with risk of cardiovascular disease in humans has been greatly expanded by recent technological advancements. However, only a fraction of the genetic risk factors have been identified and characterized so far. A major problem is that only a small fraction of the genome, the one occupied by protein-coding genes, is understood in terms of its function. Therefore, we can only predict the harmful effects of genetic variations occurring within this fraction. However, the vast majority of sequence variants associated to disease reside elsewhere in the genome. Thus, it is crucial that the non-coding functional genome (regulatory genome) be discovered and characterized. This project will use state-of-the-art technologies to identify the functional, non-coding human genome that controls formation of the outflow tract of the heart and the great vessels. We will then link the identified human regulatory information to known genetic variations associated to cardiovascular disease risk, and to available data from our collaborators on congenital heart disease (CHD). Our results will be stored into a searchable, open-access web application to facilitate their clinical translation. We expect that the results of this project will lead to the discovery of genetic variants associated to congenital heart disease and clinical phenotypes disease risk, and will eventually expand diagnostic and therapeutic capacities.

Technical Summary

Regulatory information controls the expression of genes, and drives development, disease and evolution. The aim of this proposal is to decode the regulatory information that controls development of the outflow tract of the heart (OFT) and great vessels in humans, and link this information to human disease. Abnormal development of the outflow tract of the heart and the great vessels can lead to congenital heart disease, and increased risk of cardiovascular disease in adulthood. We will: (1) identify the regulatory regions that control the formation of the OFT and the great vessels in mouse, integrating a developmental time course of chromatin modifications, transcription factors binding and gene expression data; (2) obtain similar sets of data from two critical developmental windows in human embryogenesis, and map the regulatory information (mouse and human) on the human genome; (3) link the identified regulatory information to human genetic variation, including genome-wide association (GWAS) signals, and available data from our collaborators on congenital heart disease (CHD). Our results will be stored into a searchable, open-access web application to facilitate wider interpretation of GWAS datasets and of rare DNA variants identified in CHD.

Planned Impact

The societal and economic impact of this project (apart from the academic ones) mainly lies in the area of human health.

Improving health and the biosciences: Translational genomic research is playing an increasingly important role in the diagnosis, monitoring, and treatment of diseases. There is no doubt that further understanding of human genome will fuel these advancements. The results of this project (identification of functional non-coding regions in the genome, which govern formation of the cardiovascular system) will lead to the discovery of genetic variants associated to disease risk. This will directly translate into a better diagnostic capacity, and ultimately into the possibility to prevent disease, or delay its onset, by appropriate changes in lifestyle or early access to drugs. The identification of the functional non-coding genome will also translate into new genetic diagnostic tools for patients with congenital heart disease. All of the above will have an important impact on society (the health and well-being of individuals and families) and public health.
Critically, we will build an extensive database, which will greatly assist in the clinical translation of the results generated in the project. This resource will be made public as an open-access web application; it will allow anybody in the world to search and identify potential links between the information generated in the project and congenital heart disease or clinical phenotypes disease risk.
From a clinical point of view, by generating novel functional insights into how the human cardiovascular system is formed, this research can lead to the identification of novel therapeutic targets and the development of pharmacological treatments.

Communications and Public Engagement: we will actively promote public awareness of how the fast advancement of genomic research is helping the diagnosis, monitoring, and treatment of diseases. While aimed at improving and preserving health, these advances also raise profound ethical, legal, and social issues related to the use (and possible abuse) of genomic information. Promoting the public understanding of genomics is therefore not only important to support research, but also to promote the changes in society that must accompany scientific and technological developments. We will endeavor to engage with the media, science festivals, schools, local communities and exhibitions to increase public awareness in the field of genomics research.

Publications


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Title Gata6 ChIP-seq in PBA/OFT 
Description ChIP-seq of Gata6 in posterior pharyngeal arches and outflow tract 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact The data has been submitted to ArrayExpress and will become publicly available pending publication of their related manuscript The data has been submitted to ArrayExpress and will become publicly available pending publication of their related manuscript: A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree by Losa et al. 
URL https://www.ebi.ac.uk/arrayexpress/
 
Title H3K27Ac ChIP-seq in PBA/OFT and BA2 
Description ChiP-seq to detect enhancers in in individual branchial/pharyngeal arches H3K27Ac ChIP-seq_E11.5 PBA/OFT_rep1 H3K27Ac ChIP-seq_E11.5 PBA/OFT_rep2 H3K27Ac ChIP-seq_E11.5 BA2_rep1 H3K27Ac ChIP-seq_E11.5 BA2_rep2 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact The data has been submitted to ArrayExpress and will become publicly available pending publication of their related manuscript: A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree by Losa et al. 
URL https://www.ebi.ac.uk/arrayexpress/
 
Title Meis ChIP-seq in BA2 and PBA/OFT 
Description ChIP-seq of Meis in individual branchial/pharyngeal arches Meis ChIP-seq_E11.5 PBA/OFT_rep1 ArrayExpress E-MTAB-5536 Meis ChIP-seq_E11.5 PBA/OFT_rep2 ArrayExpress E-MTAB-5536 Meis ChIP-seq_E11.5 BA2_rep1 ArrayExpress E-MTAB-5536 Meis ChIP-seq_E11.5 BA2_rep2 ArrayExpress E-MTAB-5536 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact The data has been submitted to ArrayExpress and will become publicly available pending publication of their related manuscript: A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree by Losa et al. 
URL https://www.ebi.ac.uk/arrayexpress/
 
Description School visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Students from Loreto College in Moss Side, Manchester were hosted at the University to perform a chick egg practical over two days. As part of their day, students had interviews with scientists and myself and my team were interviewed by the students on our career, e.g. what we studied, where we worked, what we discovered and what choices we made as part of our career as scientists
Year(s) Of Engagement Activity 2013,2014