Contribution of sex-specific epigenetic modifications to cardiac hypertrophy
Final Report Abstract
While it is well known that gender and age have a major impact on the onset and progression of various diseases in humans, most animal studies were carried out in male adolescent rodents only. To better characterize the influence of sex on the aging heart on a molecular basis, we compare strain, sex and age effects on H3K4me3 and gene expression in the rat. Heart left ventricle tissue was derived from Spontaneously Hypertensive Rats (SHR/Ola), a well-established model for left ventricular hypertrophy and hypertension, and Brown Norway rats (BN.Lx) both sexes each between 1.5 and 12 months of age. Overall, there was a strong positive correlation between H3K4me3 and gene expression patterns. While strain and age differences in H3K4me3 marks had larger fold changes and where mostly shared between experimental groups, autosomal sex differences were less observed and very variable between strains and ages. Most sex-specific histone methylation marks were detected in 12 mo old SHR with a majority of decreased marks in males. Associated genes such as Myh6 and Tnni3 were enriched in heart function and development gene ontology terms and 70 % showed a positive correlation with gene expression patterns on a single gene basis. Transcription factor binding site enrichment analysis revealed the heart transcription factors SRF and MEF2A as well as nuclear hormone receptors to be likely involved in this sex- and age-responsive regulation of H3K4me3 marks in SHR. Integrating cardiac H3K4me3 age and sex effects in two rat strains revealed a set of heart function related candidates which would not have been identified with gene expression data alone and might be involved in sex-specific adaptations related to left ventricular hypertrophy.
Publications
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A transacting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467 (7314): 460-464 (2010)
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Alternative splicing signatures in RNA-seq data: percent spliced in (PSI). Current Protocols in Human Genetics 87: 11.16.1-11.16.14 (2015)
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Translational regulation shapes the molecular landscape of complex disease phenotypes. Nature Communications 6: 7200 (2015)
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Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Science Translational Medicine 7 (270): 270ra6 (2015)
Roberts A.M.; Ware J.S.; Herman D.S.; Schafer S.; Baksi J.; Bick A.G.; Buchan R.J.; Walsh R.; John S.; Wilkinson S.; Mazzarotto F.; Felkin L.E.; Gong S.; MacArthur J.A.L.; Cunningham F.; Flannick J.; Gabriel S.B.; Altshuler D.M.; Macdonald P.S.; Heinig M.; Keogh A.M.; Hayward C.S.; Banner N.R.; Pennell D.J.; O'Regan D.P.; San T.R.; de Marvao A.; Dawes T.J.W.; Gulati A.; Birks E.J.; Yacoub M.H.; Radke M.; Gotthardt M.; Wilson J.G.; O'Donnell C.J.; Prasad S.K.; Barton P.J.R.; Fatkin D.; Hubner N.; Seidman J.G.; Seidman C.E.; Cook S.A.
