title: 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.forename: Bernard
authors.initials: B
authors.lastname: Thienpont
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.forename: Emma Louise
authors.initials: EL
authors.lastname: Robinson
authors.forename: Hanneke
authors.initials: H
authors.lastname: Okkenhaug
authors.forename: Elena
authors.initials: E
authors.lastname: Loche
authors.forename: Arianna
authors.initials: A
authors.lastname: Ferrini
authors.forename: Patrick
authors.initials: P
authors.lastname: Brien
authors.forename: Kanar
authors.initials: K
authors.lastname: Alkass
authors.forename: Antonio
authors.initials: A
authors.lastname: Tomasso
authors.forename: Asmita
authors.initials: A
authors.lastname: Agrawal
authors.forename: Olaf
authors.initials: O
authors.lastname: Bergmann
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Wolf
authors.initials: W
authors.lastname: Reik
authors.forename: Hywel Llewelyn
authors.initials: HL
authors.lastname: Roderick
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D044127:Epigenesis, Genetic; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C000591813:MIRN-217 microRNA, mouse; D035683:MicroRNAs; C533711:G9a protein, mouse; C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase