Research

Cardiovascular diseases (CVDs) including heart failure and atrial fibrillation are major leading causes of morbidity and mortality worldwide. The overall goal of our research is to identify and characterize transcriptional and epigenetic factors, molecular pathways as well as regulatory elements, e.g. enhancers that could be targeted to prevent disease progression, lead to remission or recovery from cardiovascular diseases.

 

We use a combination of single cell epigenomic/multiomics technologies, mouse models and functional perturbation in cell culture models to
(1) untangle and modify cardiac cell-type resolved gene regulation underlying cardiovascular diseases.

​(2) dissect cell-cell communications between cardiac cell types.

​(3) reveal the molecular function of genetic variants associated with cardiovascular diseases.

 

We hope that our research can help to develop new personalized therapeutic strategies for CVDs.

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The heart is a complex organ comprising a broad spectrum of specialized cardiovascular cell types that work closely together to ensure proper cardiac function. Spatiotemporal and cell-type-specific gene expression patterns are controlled by non-coding cis regulatory elements in the genome such as enhancers and promoters. These regions and their activation state are characterized by distinct combinations of epigenetic modifications including histone modifications and DNA methlyation. ​

Mutations in transcription factors and chromatin regulators can result in CVD and the majority of genetic variants associated with risk of CVDs are overlapping regulatory elements in the non-coding parts of the genome. CVDs are associated with structural remodelling, extensive transcriptional adaptations as well as changes in enhancer activity and histone modification profiles. However, despite progress in recent years the detailed transcriptional and epigenetic mechanisms underlying CVDs remain to be defined.

Single Cell Epigenomics and Multiomics

We optimize and adapt single-cell epigenomics and multiomics workflows to dissect gene regulation and epigenetic mechanisms in development and disease for diverse sample types. We integrate tools and datasets for a comprehensive view of gene regulation across multiple molecular layers including transcriptome, chromatin accessibility and histone modifications.

We are always excited about collaborations to apply these experimental platforms to different research questions outside the heart.  

Atrial Fibrillation and Heart Failure

We are particularly interested to reveal the detailed cell-type-specific epigenetic, gene regulatory and transcriptional changes underlying disease pathogenesis of two common cardiovascular diseases, atrial fibrillation and heart failure with reduced ejection fraction.  

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. Current treatment options for AF show limited efficacy in maintaining sinus rhythm or are not suitable in all patients and 1 on 4 patients will progress from paroxysmal, intermittent AF to permanent AF within 5 years.

Heart failure with reduced ejection fraction (HFrEF) affects more than 10 Million people wordwide. Pharmacological therapy reduces morbidity and mortality of heart failure, but no current therapy specifically targets the heart muscle and a transplant is the only cure. Mechanical unloading in patients with end-stage heart failure leads in some patients to improved heart function and partial remission of heart failure. 

Congenital Heart Disease

We are very interested to understand the molecular underpinnings of congenital heart diseases (CHD). CHD represent the number one birth defects with a prevalence of ~0.8 % and improved survival of CHD patients has resulted in a growing adult CHD patient population. Proper cardiac development and heart function rely on the precise spatiotemporal control of gene expression. De novo mutations are often found in coding regions of transcription factors and histone modifying enzymes and a large fraction of genetic variants overlaps non-coding regulatory elements of the genome. 

Key technologies

  • Single Cell Genomics (Single cell ATAC-seq, single cell/nucleus RNA-seq, single cell/nucleus Multiomics)

  • Epigenomics (ATAC-seq, ChIP-seq, CUT&Tag/RUN)

  • Functional Genomics (CRISPR perturbation)

  • Mouse models and in vitro cell culture models