Group leaders: Eileen Furlong and Johannes Backs

Our research interest

Our team focuses on both fundamental and translational aspects of chromatin biology in the context of human heart development and disease including cardiomyopathies and acquired forms of acute/chronic heart failure. These heart diseases represent the most frequent underlying cause of death in western countries and thereby need an in depth investigation to develop new approaches to pave the way towards new translational approaches. Specific areas of interest include the mechanisms of epigenetic regulation down to the single cell level and the generation of tractable human in vitro 3D models (cardioids) that recapitulate the early steps of heart development and disease.

Background

Although a number of morphological heart defects can be addressed surgically, the genetic causes persist, and eventually result in heart failure and arrhythmias in adults. Mutations in transcription factors or chromatin modifiers lead to congenital heart disease, but very little is known about the pathomechanisms linking the specific genetic causes to cardiac dysfunction in adults. Mutations in chromatin modifying enzymes do not only cause neonatal and adult heart disease due to misregulation of gene expression, but also by stress-induced regulatory mechanisms that lead to secondarily heart disease.

Goals

This program aims to develop a human in vitro 3D model that recapitulates the early steps of heart development to form a 3D heart tube, which we will further exploit to make more complex heart organoids. Such a model will provide a genetically tractable system to study the molecular basis of both human heart development and genetic heart disease, especially when combined with gene perturbations and state-of-the-art single-cell technologies. We will use single-cell approaches (such as scATAC-seq) to follow the developmental trajectories of iPS cell differentiation with different protocols to develop a 3D system that best recapticulates human heart development. Having such 3D heart models in hand will enable a characterization of the functional impact of disease associated genetic variants. Chromatin remodeling will be assessed after genetic perturbations and also upon inflammatory stress, which we previously discovered leads to an acute de-compaction of chromatin. The combined expertise of both groups may lead to synergies to discover fundamental principles with translational potential to combat inherited and acquired heart disease.