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 1

H3K9me2 is decreased in CMs upon AB in rats.

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H3K9me2 is decreased in CMs upon AB in rats. (A) Graphs show LV/BW ratio...
(A) Graphs show LV/BW ratio, normalized to sham or control (mg/g); EF percentage; and ratio of LV lumen diameter to myocardial wall thickness at end-diastole. n = 7, 9, 6, and 8 animals for control, exercise, sham, and AB, respectively. (B) M-mode echocardiogram showing, at end-diastole, the LV diameter (LVDd) and thickness of the posterior wall (PWd) and of the interventricular septum (IVSd). Horizontal scale bars: 0.1 second; vertical scale bars: 2 mm. (C) qRT-PCR showing expression of Nppa, Nppb, Myh6, and Myh7 in the LV. (D) Volcano plot of differential markings by H3K9me2 and H3K27me3 of, respectively, LOCKs and BLOCs in PCM1+ nuclei upon pathological (left) and physiological (right) hypertrophy, as determined by ChIP-seq. Red and green dots represent regions enriched and depleted upon hypertrophy (FDR <10%; >20% change). (E) Plots show H3K9me2 signal in PCM1+ nuclei, determined by immunofluorescence analysis of the LV from AB, sham-operated, exercise, and control animals (n = 4, 5, 3, and 5, respectively). Representative confocal immunofluorescence images show staining for wheat germ agglutinin (WGA, red) and PCM1 (white), and H3K9me2 (green) in the LV. Scale bars: 50 μm. Error bars indicate the SEM. n = 5 (C) and 4 (D) replicates. *P < 0.05, **P < 0.01, and ***P < 0.001, by Student’s t test (A and C) and nested ANOVA (E).