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 8

Downregulation of Ehmt1/2 by miR-217 is required for hypertrophy induction in vivo.

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Downregulation of Ehmt1/2 by miR-217 is required for hypertrophy inducti...
(A) Effect of miR-217 antagomir or scramble treatment upon expression of Ehmt1 and Ehmt2 in hearts from sham- or AB-operated mice 2 weeks after surgery. (B) M-mode echocardiogram from parasternal location of mice treated as in A. Indicated are, at end-diastole, the LV diameter (LVDd) and the thickness of the posterior wall (PWd) and of the interventricular septum (IVSd). Horizontal scale: 0.1 second; vertical scale: 2 mm. (C) LV mass as estimated by echocardiography (echo) 1 day after AB (before administration of antagomirs) and 2 weeks after AB (n = 5 for miR-217– and 8 for scramble-injected animals). (D) LV/BW ratio, LV lumen/wall diameter ratio, and EF of hearts treated as in A (n = 4, 4, 8, 5 for the indicated conditions). (E) Expression of Nppa, Nppb, Myh6, and Myh7 in hearts treated as in A. (F) Schematic of miR-217 regulation of Ehmt expression and pathological hypertrophy. ***P < 0.001, **P < 0.01, *P < 0.05, and #P = 0.07, by Student’s t test. Error bars in A and E represent the mean ± SEM of 4 (sham conditions), 8 (AB plus αScramble), or 6 (AB plus αmiR-217) mice.