Contribution of sex-specific epigenetic modifications to cardiac hypertrophy

• Antragsteller: Professor Dr. Norbert Hübner
• Fachliche Zuordnung: Kardiologie, Angiologie
• Förderung: Förderung von 2011 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 60843499

Despite being strongly related to hypertension, left ventricular (LV) hypertrophy remains associated with excess risk for adverse cardiovascular morbid and fatal outcomes after adjusting for blood pressure. Observational data suggest gender-specific control of myocardial adaptations to hemodynamic overload and a more rapid induction of LV hypertrophy during myocardial dysfunction in male subjects. As the epigenome has profound effects on genome activity it may represent an important contributor to sex-specific differences in hypertension-associated hypertrophy. The proportion of sex-specific phenotypic variability ascribed to pure epigenetic factors remains unclear. We will study histone modification marks in male and female rats. We will use a segregating rat population which exhibits marked hypertension and myocardial hypertrophy and its normotensive reference. This panel of 30 recombinant inbred (RI) rat strains will be utilized to study sexspecific allelic effects on histone modification marks throughout male and female LV tissue. We will perform chromatin immunoprecipitation of H3K4me3 and H3K27me3 marks and next generation sequencing to generate genome wide datasets in the RI inbred rats. This RI panel has previously been genotyped at high density and progenitors have been completely sequenced providing a full picture of segregating variants at nucleotide level resolution. Through integration of existing genome-wide gene expression data from LV tissue across the RI strains we will be able to test association of sex-specific quantitative differences in histone methylation marks with sex-specific consequences on gene expression levels. The set of identified candidates may play an important role in sex-specific adaptations related to hypertension associated hypertrophy and heart failure.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 1054: Sex-specific mechanisms in myocardial hypertrophy