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 5

Suppression of EHMTs induces hypertrophy in vitro.

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Suppression of EHMTs induces hypertrophy in vitro. (A and B) Protein syn...
(A and B) Protein synthesis (A) and qRT-PCR for Nppa, Nppb, Myh6, and Myh7 (B) in primary NRVMs exposed for 48 hours to ET-1 or vehicle (water) and in response to EHMT1/2 inhibition (A-366). (C) Immunofluorescence staining for α-actinin (white) and ANF (green) in NRVMs treated with or without ET-1 and/or A-366. Nuclei were counterstained with DAPI (blue). Scale bars: 20 μm. (D) Immunofluorescence signal intensities of perinuclear ANF (shown is 1 representative experiment from 4 repeats). (E and F) Protein synthesis analysis by 3H-leucine incorporation (E) and Nppa, Nppb, Myh6, and Myh7 expression (F) in NRVMs transduced with empty or EHMT2 adenovirus 8 hours prior to agonist addition (ET-1 or water). Cells were assayed 48 hours after agonist addition. Note that the hypertrophic response appears dampened in transduced NRVMs compared with nontransduced NRVMs in A and B. Error bars in A, B, E, and F represent the mean ± SEM. n = 5 biological replicates. *P < 0.05,**P < 0.01, and ***P < 0.001, by Student’s t test.