Project description
Staying young at heart – a lesson from zebrafish on epigenetic inheritance
Some animals, including zebrafish, have the incredible ability to regenerate their injured heart. Epigenetic remodeling may play a pivotal role in the process and the environment can also influence this capacity. Transgenerational epigenetic inheritance (TEI) is the transmission of experiences from parents to their offspring through the gametes, without alteration of the primary structure of DNA. Changes in DNA methylation, histone modifications and non-coding RNAs are associated with TEI. The EU-funded TransReg project studies the epigenetic inheritance of organ regeneration using the zebrafish model. The aim of the project is to assess whether cardiac injury causes epigenetic modifications in sperm and if offspring from injured parental fish display altered heart regeneration. The findings will elucidate the origins of cardiovascular disease and define epigenetic priming as a basis for regeneration.
Objective
While myocardial infarction leads to adverse ventricular remodeling ultimately causing heart failure in humans, some animals, including zebrafish can regenerate the injured heart. We recently revealed a high degree of plasticity in cardiomyocyte subpopulations involved in the reconstruction of the injured heart. The gene regulatory network involved in heart regeneration is starting to be elucidated and epigenetic remodeling has been suggested to play a pivotal role during this process. Similarly it is known that the environment can influence the regenerative capacity but whether such an effect can be transmitted from one generation to the next has not been addressed. This mechanism is called transgenerational epigenetic inheritance (TEI) and describes the transfer of experiences from parents to their offspring through the gametes, independent on changes in DNA sequence. TEI has also been described in humans: starvation suffered by grandparents affects the metabolism of grandchildren. TEI is also relevant to organ injury: in rats, offspring from parents exposed to liver toxicants revealed reduced hepatic fibrosis in response to the same injury. Changes in DNA methylation, histone modifications and non-coding RNAs have been associated to TEI. We aim to describe for the first time epigenetic inheritance of organ regeneration and unravel its underlying mechanism using the zebrafish model. We will assess whether cardiac injury elicits epigenetic modifications in sperm and determine if offspring from injured parental fish reveal altered heart regeneration. Genetic models will be developed for functional assessment of identified modifications. We will also further analyze cell plasticity during heart regeneration and address whether hearts regenerated from different progenitors respond equally well to further injuries. Our expected findings will constitute a paradigm shift on the origins of cardiovascular disease and define epigenetic priming as a basis for regeneration.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
3012 Bern
Switzerland