The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy
Bernard Thienpont, … , Wolf Reik, Hywel Llewelyn Roderick
Bernard Thienpont, … , Wolf Reik, Hywel Llewelyn Roderick
Published November 28, 2016
Citation Information: J Clin Invest. 2017;127(1):335-348. https://doi.org/10.1172/JCI88353.
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Research Article Cardiology Cell biology

The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy

Abstract

Cardiac hypertrophic growth in response to pathological cues is associated with reexpression of fetal genes and decreased cardiac function and is often a precursor to heart failure. In contrast, physiologically induced hypertrophy is adaptive, resulting in improved cardiac function. The processes that selectively induce these hypertrophic states are poorly understood. Here, we have profiled 2 repressive epigenetic marks, H3K9me2 and H3K27me3, which are involved in stable cellular differentiation, specifically in cardiomyocytes from physiologically and pathologically hypertrophied rat hearts, and correlated these marks with their associated transcriptomes. This analysis revealed the pervasive loss of euchromatic H3K9me2 as a conserved feature of pathological hypertrophy that was associated with reexpression of fetal genes. In hypertrophy, H3K9me2 was reduced following a miR-217–mediated decrease in expression of the H3K9 dimethyltransferases EHMT1 and EHMT2 (EHMT1/2). miR-217–mediated, genetic, or pharmacological inactivation of EHMT1/2 was sufficient to promote pathological hypertrophy and fetal gene reexpression, while suppression of this pathway protected against pathological hypertrophy both in vitro and in mice. Thus, we have established a conserved mechanism involving a departure of the cardiomyocyte epigenome from its adult cellular identity to a reprogrammed state that is accompanied by reexpression of fetal genes and pathological hypertrophy. These results suggest that targeting miR-217 and EHMT1/2 to prevent H3K9 methylation loss is a viable therapeutic approach for the treatment of heart disease.

Authors

Bernard Thienpont, Jan Magnus Aronsen, Emma Louise Robinson, Hanneke Okkenhaug, Elena Loche, Arianna Ferrini, Patrick Brien, Kanar Alkass, Antonio Tomasso, Asmita Agrawal, Olaf Bergmann, Ivar Sjaastad, Wolf Reik, Hywel Llewelyn Roderick

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Figure 3

Hypertrophy-associated transcriptomic changes in flow-sorted rat CMs.

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Hypertrophy-associated transcriptomic changes in flow-sorted rat CMs. (A...
(A and B) Violin plots illustrating the gene-wise relation between RNA expression and H3K9me2 (A) or H3K27me3 (B). Data were quantified per gene and are represented as log2((fragments + 1) per kb per million) (FPKM). (C and D) Gene expression, represented as fragments per million (FPM), in PCM1+ nuclei sorted from hypertrophied and control hearts. Highlighted are the genes that were significantly upregulated (green) and downregulated (red) (FDR <10%) after 6 weeks of hypertrophy induction, with characteristic genes indicated. (E) Fractions of differentially expressed genes (FDR<10%, difference >20%) in LOCKs with H3K9me2 loss or gain upon AB. (F) Selected ontological terms significantly enriched among genes significantly up- or downregulated in PCM1+ nuclei upon exercise and AB. The gray box before each bar represents the P value of enrichment; there are no boxes for P values greater than 0.05. (G and H) Characterization of genes displaying loss of H3K9me2 upon AB. (G) Graph represents the fraction of genes that were upregulated during the in vitro differentiation of ESCs into CMs, as determined by Wamstad and colleagues (18). (H) Graph shows the fraction of genes that were downregulated in the adult versus newborn heart (19). Data for G and H were from the mouse genome. For comparisons with the rat genome, analyses were limited to genes having 1-to-1 paralogs between both species. n = 4. *P < 0.05 and ***P < 0.001, by χ2 test.