GeneRegulatory Networks in Cardiac Hypertrophy and Failure

Coordinator:    Prof. Dr. Norbert Hübner
Institution: Max-Delbrück-Centrum for Molecular Medicine Berlin-Buch, ExperimentalGenetics of Cardiovascular Diseases
The Project aimed at studying regulatory networks in relation to cardiac hypertrophy and heart failure. Myocardial-specific physiological pathways were studied through combination of gene expression data from various tissues in recombinant inbred rat strains (RIs). We focused on subtle perturbations induced by naturally occurring DNA variations that are highly multifactorial and, in combination with environmental conditions, explain the majority of complex trait variation in populations.

We sequenced the complete genome of the spontaneously hypertensive rat (SHR) using next generation sequencing technology. This near complete catalogue of genomic differences between two extensively studied rat strains, BN and SHR, provides the starting point for complete elucidation, at the molecular level, of the physiological and pathophysiological phenotypic differences between individuals from these strains.

We used integrated genome-wide approaches across tissues in the BXH/HXB-panel of recombinant inbred rat strains to identify gene networks and the loci underlying their regulation. We identified a gene network centered on the interferon response transcription factor IRF7, which is regulated in multiple tissues by a single locus on rat chromosome 15, represents a molecular biomarker for macrophage infiltration of tissues, and is conserved in human monocytes (Heinig et al., 2010).

By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats (Guo et al., 2012).

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