Project description
Titin as a link to epigenetic remodelling in the aetiology of heart disease
The aetiology of heart disease relates to altered contractility and cardiac tissue tension and is characterised by changes in gene expression and epigenetic remodelling. A sarcomere is the main contractile unit in the striated muscle, where the giant protein titin is the major source of cardiac passive tension. The EU-funded TiGER project aims to investigate the hypothesis that the titin passive tension is transmitted to the nucleus and the mechano-sensitive nuclear lamina, which affects chromatin structure and gene expression, similar to cytoskeleton passive tension in non-muscle cells. The project will use human cardiomyocytes derived from induced pluripotent stem cells, genetically engineered to have either a low or high titin-derived passive tension, followed by the analysis of chromatin remodelling factors.
Objective
Heart disease is a staggering clinical and public health problem and the leading cause of death for both men and women in Western countries. The underlying pathomechanism of nearly all aetiologies relates to altered contractility and cardiac tissue tension but also gene expression changes and epigenomic remodelling. Within the sarcomere, the fundamental contractile unit in striated muscle, the giant protein titin is the major source of cardiac passive tension. Since sarcomeres are connected to the nucleus, I hypothesise that titin passive tension is transmitted to the nucleus and sensed by the mechano-sensitive nuclear lamina, affecting chromatin structure and gene expression, similar to cytoskeleton passive tension in nonmuscle cells. I will test this hypothesis in human cardiomyocytes derived from induced pluripotent stem cells (hiPSC-CMs) with either a low or high titin-derived passive tension by editing the titin gene locus. I will also investigate whether changes of titin tension affect sarcomere-resident chromatin remodellers: Smyd1, Smyd2, and HP1γ. Combining fluorescence and super-resolution imaging with chromatin-immunoprecipitation sequencing and RNA sequencing, I will delineate a comprehensive map of titin-derived epigenetic remodelling in hiPSC-CMs. The TiGER project will dissect a complex biophysical mechanism leveraging on hiPSC-CMs as they represent an exceptional platform to unveil human cardiac-specific phenomena that require extensive gene editing, culture, and imaging. As titin-derived passive tension changes during development, physiology, and disease, TiGER’s results could have major implications for cardiac pathophysiology and could unlock future compelling research avenues. I will explore this novel role for titin as an epigenetic remodeller under the supervision of Prof. Dr. Gotthardt, a world-leading expert of cardiac mechanotransduction and titin at the Max Delbrück Center (MDC) in Berlin.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- medical and health scienceshealth sciencespublic health
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesbasic medicinephysiologypathophysiology
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- medical and health sciencesmedical biotechnologycells technologiesstem cells
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
13125 Berlin
Germany