Research

Medical Genomics and Genetics of Cardiovascular and Metabolic Diseases

 

Genome wide approaches have been very successful in identifying regulatory loci influencing complex traits. However, many genetic mechanisms underlying complex diseases and their molecular pathways remain unknown. Our group is interested in identifying the underlying causes of common cardiovascular and metabolic diseases. We combine high-throughput technologies and computational approaches for comprehensive analyses of gene networks and genomic mechanisms in cardiovascular phenotypes. We primarily use the rat as model organism.

 

Research aim:

We aim to understand biological systems by studying perturbations which occur naturally as DNA variation or as environmental conditions that are relevant to complex diseases. In particular, we study gene networks underlying cardiometabolic and inflammatory phenotypes in the rat, aiming at the translation of the findings to the molecular pathology of related human disorders.

 

Current activities and methods:

We use recombinant inbred (RI) strains derived from BN and SHR, the latter being a well-established model for cardiovascular and metabolic disease. We carried out genome sequencing and SNP genotyping of the RI. Using RNA-Seq and ChIP-Seq data we identified causative variants underlying the regulation of gene expression, splicing, miRNAs, and histone modifications in collaboration with several BIMSB groups (Chen, Landthaler, Rajewsky, Selbach). Further, we apply several molecular biology techniques for experimental validation. To characterize the interaction of the splicing factor RBM20 with its RNA targets, we use PAR-CLIP and TEV cleavage assays. Another powerful rat model is the heterogenous stock (HS) of more than 1400 animals originally derived from 8 founder animals. Using the HS rats we recently identified candidate genes that may be involved in the formation of aortic lesions, metabolic disorders and heart disease.

 

Perspective and future directions:

Integrating genomic, epigenomic and transcriptomic data will enable us to identify pathways leading to cardiovascular and metabolic phenotypes. Obtaining multi-level datasets will facilitate the translation of findings from the rat to clinically relevant disease phenotypes in humans.

 

 

List of participants and related projects:

Norbert Hübner 

Principal Investigator

Matthias Heinig

Christin Mieth

 

Natural variation of histone modifications – We study the interplay between genetic variability and histone modifications in male and female rats. Thereby, we can distinguish sex-specific genetic and environmental influences on histone modification levels.

Samreen Falak



Mapping complex traits in HS rats – We use a large scale rat population (n > 1400) to identify genes underlying arterial internal elastic lamina lesions. Recently, we found a QTL for aortic lesions encompassing a protease inhibitor gene.

Eleonora Adami

Anja Bauerfeind

Henrike Maatz

Sebastian Schäfer

 

Genetic causes of cardiomyopathy and heart failure – We did RNA-Seq and whole genome sequencing in patients with dilated cardio­myopathy (DCM) and identified several potential candidate genes. We currently work on the molecular characterization of a mutated RNA binding motif protein that is associated with DCM phenotype in rat and human.