TiGER · Titin can govern epigenetic remodelling
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-01-01 → 2023-12-31
- EU contribution
- €174,806
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Titin can govern epigenetic remodelling
Heart diseases are the leading cause of death in Western countries for both men and women. These diseases are often irreversible and get worse over time. One of the reasons behind these diseases is the way the heart contracts and the tension in the heart tissue. There is a protein called titin, which is very large and present in all muscle cells. Titin plays a major role in determining the tension in the heart tissue. Titin has a special part called N2B that acts like a spring and is only found in heart cells. When the N2B part is missing in mice, their hearts become even stiffer and smaller. We still have many questions about how the N2B part affects heart cells. We used cardiac cell of human origin to study the function of the N2B sequence in titin. We removed the N2B sequence from the gene in the cells and studied the effects on contraction, expression of genes and cell structure. This research is important to understand how the N2B part of titin affects the human heart in both normal and diseased conditions and therefore will help designing new therapeutic strategies to combat cardiac diseases.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC) · BerlinCoordinatorGermany
Links
- View on CORDIS
- DOI: 10.3030/101030677
- https://www.mdc-berlin.de/news/news/unraveling-mysteries-heartbeat
Data: CORDIS, © European Union