The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy
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
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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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 7

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

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Downregulation of Ehmt1/2 by miR-217 is required for hypertrophy inducti...
(A and B) RLU of luciferase constructs harboring the 3′-UTR of EHMT1 or EHMT2, transfected into NRVMs treated with water or ET-1 (A), or into HEK293 cells transfected with scrambled or miR-217 mimic (B). (C and D) Expression of miR-217 in rat CM nuclei sorted from sham-operated, AB-operated, control, or exercised hearts (C), and in NRVMs treated for 48 hours with ET-1, IGF-1, or water (D). (E) Expression of Ehmt1 and Ehmt2 in NRVMs transfected with scrambled or miR-217 mimic for 48 hours and treated for 48 hours with ET-1 or water. (F) RLU of luciferase constructs harboring the 3′-UTR of Ehmt1 or Ehmt2, transfected into NRVMs treated with control (anti-scramble; αScr) or miR-217 antagomirs (anti–miR-217; αmiR-217). Shown are the RLU in response to 48 hours of exposure to ET-1 relative to water-treated controls. (G) Expression of Nppa, Nppb, Myh6, and Myh7 in NRVMs treated with control or miR-217 antagomirs and exposed for 48 hours to water or ET-1. *P < 0.05, **P < 0.01, and ***P < 0.001, by Student’s t test. Error bars represent the mean ± SEM of 5 independent experiments.