Abstract 10833: Comprehensive Quantitative Epigenome Mapping Reveals the Differential Induction of Histone H3 Lysine 4 Trimethylation Marks in Pressure-overloaded Murine Hearts
Background Although recent findings have revealed that environmental stimuli alter both transcriptional and epigenetic states, it remains uncertain whether both transcriptional changes and active epigenetic marks are coordinately regulated under environmental stimuli.
Methods and Results In the murine pressure-overloaded hearts induced by transaortic constriction in a week and the sham-operated hearts (each in duplicate), we analyzed active histone marks and expression profiles using histone H3 Lysine 4 trimethylation (H3K4me3) ChIP-sequence and RNA-sequence. We developed a normalizing and quantification algorithm for H3K4me3 marks around transcription start site which enables absolute comparison between the pathological conditions. Hypertrophic stimuli altered global H3K4me3 states along with transcriptional changes. However, individual H3K4me3 mark was not necessarily correlated with transcriptional change but differentially regulated depending on gene clusters. We filtered 148 and 141 genes with decreased and increased H3K4me3 marks, respectively. Intriguingly, H3K4me3 marks were markedly and immediately depleted at the genes involved in cardiac contraction especially with high absolute expression values, accompanied with transcriptional down-regulation (e.g. Myh6, Pln, Tnni3). On the other hand, H3K4me3 marks were increased in the genes mainly involved in protein translation including many ribosomal genes (e.g. Eef2, Rpl8, Rpl9) and particularly in Myc transcription factor, although transcriptionally up-regulated genes were largely associated with wound and inflammatory response. Unexpectedly, H3K4me3 in transcriptionally up-regulated cardiac fetal genes did not change. Most of the genes with increased H3K4me3 in failing hearts were not cardiac specific. However, we identified exceptionally cardiac specific genes with enhanced H3K4me3 associated with cytoskeletal function.
Conclusion Genome-wide analysis using quantitative epigenome mapping combined with expression profiling revealed the differential induction of H3K4me3 states due to external hypertrophic stimuli in failing hearts. These methods combined with cardiac specificity could be an attractive novel screening approach.
- © 2012 by American Heart Association, Inc.