The Laboratories of Experimental Cardiology and Functional Epigenetics are recruiting a PhD student to work on an exciting project to develop new tools to analyse and investigate the changes in the methylome of cardiac cells during age and pathology (atrial fibrillation, heart Failure, metabolic syndrome). This position is supported by a recent European Research Agency co-fund grant (ERA4Health) with partners in Spain and France and a Flemish Research Council (FWO) grant awarded together with UAntwerp.
Cardiovascular diseases, including heart failure and atrial fibrillation are the leading cause of death worldwide. With age being their greatest risk factor, prevalence will increase over the coming decades with the changing demographic. Cardiac remodelling is a product of the remodelling of the diverse cell types of the heart, including cardiomyocytes, fibroblasts and immune cells that leads to diminished contraction, increased fibrosis and greater arrhythmia. Recent single cell sequencing analysis has identified how transcriptomic changes, shifts in cell type proportions and phenotypes as well as alterations in cell-cell interactions contribute to the altered function of the heart. The regulatory mechanisms underlying these changes across the cell types of the heart are however unclear but involve remodelling of the epigenome, of which DNA methylation is a key contributor. Our research has identified unique properties of the methylome of cardiomyocytes. The post-mitotic nature of these cardiomyocytes would indicate that loss of DNAme with age is via an active process, which we now identify. Using Aging Clock-associated methylated CpGs, we show that cardiomyocytes are younger than other cardiac cell types, but become older with disease. Despite these new and exciting findings, current analysis methods do not allow access to the methylomes of all cardiac cell types. In the absence of a cardiac specific aging clock, insights into the involvement of the methylome in heart ageing and the interventions that affect this trajectory cannot be resolved. Moreover, and preventing prediction of cardiac health from the blood, the relationship between the cardiac methylome and blood is not established.
In this project, we will develop or implement and apply advanced bioinformatics and computational epigenomics approaches for single-cell DNA methylome analysis of human heart tissue. The PhD candidate will establish new analytical strategies and tools for the integration, processing, and interpretation of large-scale single-cell DNA methylome datasets across healthy and diseased human hearts. These approaches will enable the generation of high-resolution ground truths for cardiac cell types and states, providing, for the first time, comprehensive DNA methylome maps of human cardiomyocytes, fibroblasts, and other cardiac cell populations during ageing and disease-associated remodelling. These will serve to enable bulk tissue deconvolution, as well as epigenetic age prediction, including the establishment of cardiac-specific DNA methylation signatures and ageing clocks. Finally, we will explore integrative analyses linking cardiac and circulating blood DNA methylomes to uncover minimally invasive biomarkers predictive of cardiac health and disease progression.
Access to over 500 human cardiac tissue samples, collected in the KU/UZ Leuven biobank together with atrial samples collected by our collaborators in Antwerp provides a unique resource for this study.
This project sits alongside others in the laboratory aimed to understand cardiac remodelling during disease and ageing.
The Laboratory of Experimental Cardiology:
The Laboratory of Experimental Cardiology sits alongside clinical and basic research groups within the Department of Cardiovascular Sciences involved in translational research investigating cardiac structural, contractile and electrical remodeling processes and the molecular mechanisms that underpin them during cardiovascular disease. The laboratory is highly international consisting of post-doctoral scientists, PhD students and technicians. We also collaborate widely with external partners to advance our research and provide opportunities for training.
The laboratory is equipped with the wide range of expertise and skills required to manipulate and probe the transcriptome/epigenome (and the mechanisms governing functions and phenotype of the heart and cardiac myocyte fate choices). These resources span across large preclinical and small animal models of cardiovascular disease, iPS cells, 10x sequencing RNA-Seq, ChiP-Seq, DNA (hydroxy)methylation analysis and analysis of excitation contraction coupling. You will receive extensive training and support in these areas. Through our excellent local and international collaborators and core facilities, you will have access to additional expertise and tools.
The Laboratory of Functional Epigenetics:
The Laboratory of Functional Epigenomics, led by Bernard Thienpont, is embedded within a highly collaborative and interdisciplinary research environment focused on understanding how epigenetic and transcriptional programs regulate cellular identity, plasticity and disease progression. The laboratory brings together an international team of post-doctoral researchers, PhD students and technical experts working at the interface of molecular biology, genomics, computational biology and translational medicine. The lab is closely connected to the Leuven Integrated Single-Cell Omics initiative (LISCO) and the Leuven Cancer Institute (LKI), providing a strong interdisciplinary network and access to cutting-edge technologies, collaborative research programs and translational cancer research expertise.
The laboratory is equipped with state-of-the-art technologies to investigate gene regulatory mechanisms and cell state dynamics at bulk and single-cell resolution. Research activities span advanced epigenomic and transcriptomic profiling approaches, including single-cell and spatial omics, CRISPR-based functional screening, chromatin accessibility and singel cell DNA methylation analyses, next-generation sequencing and integrative computational modeling. Experimental platforms include ES cell differentiation systems, primary patient-derived samples and in vitro disease models. Researchers within the laboratory receive broad training and support in experimental design, cutting-edge molecular technologies and data-driven biology, while benefiting from access to outstanding local and international collaborators, core facilities and interdisciplinary expertise.
The Departments of Cardiovascular Sciences and Human Genetics:
The Departments are situated in the Biomedical Campus of KU Leuven. We together possess the entire range of competences from basic science, over pre-clinical modeling to applied clinical and epidemiological research, taking a systems approach to the complexity of cardiovascular disorders.
The University:
KU Leuven offers a stimulating environment for international students and support for junior scientists to achieve their ambitions and in career development. Founded in 1425, it is Belgium’s largest university, currently featuring among the best universities in the world according to the Times Higher Education and recently ranked as Europe’s most innovative for the third year in a row. More information about the university can be found here.
It is located in Leuven, a small but vibrant student town by the river Dijle, where centuries of history meet cutting-edge science. Leuven is located 25km from Brussels, the beating heart of Europe, and is easily accessible by plane (through Brussels Airport) and by public transport. More information about life in Leuven can be found here.
Website unit
Project
You will develop your own project on to develop new pipelines for analysis of DNA in cardiac cells and using these to determine how DNA methylation changes and influences cardiac remodelling during aging and disease.
You will collaborate with members of the Functional Epigenetics and Experimental Cardiology laboratories, as well as with national and international collaborators involved.
You will be expected to develop expertise in areas necessary for successful progress of your project.
You will be expected to present your work at conferences, lab meeting, and departmental meetings.
Profile
You are motivated, have an enquiring mind and are excited by science.
You are experienced in NGS approaches, including RNA-Seq. Experience in single cell methods is also an advantage.
Experience with NGS data processing and working knowledge of R, Python and bioconductor packages are a strong advantage.
You have experience in cell biology and mouse models/experiments and are driven to establish mechanisms controlling cell function.
You have a demonstrated ability to perform high-level biomedical research.
You enjoy collaborating with your colleagues and externally to scientific advance.
You hold a PhD degree in Biomedical Sciences, Cell Biology, Biochemistry or other similar domain of life sciences with working knowledge in relevant areas.
You are a team player with excellent written and oral communication skills in English
You are an independent thinker who can drive a project forward.
You enjoy presenting your data to collaborators and to the community at scientific meetings.
You perform your research to the highest standards and integrity.
Offer
A fully funded PhD position for 4 years.
A stimulating and supportive environment in which you acquire expertise as a multidisciplinary researcher.
Opportunity to develop yourself as an independent researcher
Opportunity to collaborate nationally and across borders.
Support to apply for independent funding from the national and international funding agencies including the Flemish Research Council (FWO) and the EU.
https://gbiomed.kuleuven.be/english/cme/research/laboratories/54213024/members-1/00048367
Interested?
Please send your CV, motivation letter and 2 recommendation letters to Prof. Dr. H. Llewelyn Roderick, Email: ([email protected]) or Prof Dr. B. Thienpont ([email protected]). Please also apply via the online portal of KU Leuven.
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