Deciphering regulatory elements as determinants of cardiovascular diseases
Title (trans.)
Caracterización de elementos reguladores implicados en enfermedades cardiovascularesAuthor
Victorino Santos, JesúsAdvisor
Manzanares Fourcade, MiguelEntity
UAM. Departamento de Bioquímica; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Date
2021-03-05Subjects
Enfermedades cardiovasculares - Malformaciones congénitas - Diagnóstico y tratamiento - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 05-03-2021Esta tesis tiene embargado el acceso al texto completo hasta el 05-03-2022
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
The non-coding genome harbors cis-regulatory elements (CRE) that control gene
expression in time and space. A tight control of transcription is of great importance,
especially during development, and CRE disruption may lead to malformations and
other congenital diseases. Genome-wide association studies (GWAS) have identified
common polymorphisms associated to multifactorial disorders in humans such as
cardiovascular diseases. The vast majority of these associations lay in non-coding
regions. Whether these thousands of risk loci affect CREs and have a functional role
in the context of disease is unknown. Cardiovascular diseases (CVDs) are common
human diseases with the highest prevalence and death rate worldwide. To date,
GWAS have linked hundreds of loci to a higher risk of developing two major CVD:
Atrial Fibrillation (AF) and Atherosclerosis. CVDs are not an exception and for most
risk loci we lack mechanistic insights into the nature of GWAS associations.
Although enhancer-reporter assays (ERAs) are a powerful tool to characterize riskassociated
enhancers, these experiments are time-consuming and the throughput is
very limited. This is in stark contrast with the outgrowing number of new
polymorphisms associated to human diseases. In this thesis, we optimized current
mouse ERA technology to achieve ~59% efficiency of transgenesis, thus enabling the
scaleup of CRE discovery. We systematically interrogated a dozen risk loci strongly
associated to AF in the search for disease-risk enhancers. Interestingly, we showed
that the PB-ERA system that we developed is able to identify negative regulators such
as silencers or insulators. Together with 3D chromatin analysis and CRISPR-mediated
perturbations, we identified the targets of AF-CREs and involved new genes in
arrhythmia susceptibility. Furthermore, we integrated transcriptomic data from an
ovine model of AF chronification. We found that GWAS and chronification data
converge on the TBX5-GJA1 axis and identified AF-enhancers regulating the cardiac
expression of both genes. These enhancers are controlled by TBX5 itself in what might
be a key feedback-loop for atrial remodeling.
Last but not least, we applied our approach to a second CVD to validate it as an
effective framework to understand the genetic contribution to human diseases. We
interrogated the locus of the pro-atherosclerotic gene PCSK9 and describe a dual
regulation for this gene in liver and cerebellum
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