DNMT3B System Dysregulation Contributes to the Hypomethylated State in Ischaemic Human Hearts

Abstract

A controversial understanding of the state of the DNA methylation machinery exists in ischaemic cardiomyopathy (ICM). Moreover, its relationship to other epigenetic alterations is incomplete. Therefore, we carried out an in-depth study of the DNA methylation process in human cardiac tissue. We showed a dysregulation of the DNA methylation machinery accordingly with the genome-wide hypomethylation that we observed: specifically, an overexpression of main genes involved in the elimination of methyl groups (TET1, SMUG1), and underexpression of molecules implicated in the maintenance of methylation (MBD2, UHRF1). By contrast, we found DNMT3B upregulation, a key molecule in the addition of methyl residues in DNA, and an underexpression of miR-133a-3p, an inhibitor of DNMT3B transcription. However, we found many relevant alterations that would counteract the upregulation observed, such as the overexpression of TRAF6, responsible for Dnmt3b degradation. Furthermore, we showed that molecules regulating Dnmts activity were altered; specifically, SAM/SAH ratio reduction. All these results are in concordance with the Dnmts normal function that we show. Our analysis revealed genome-wide hypomethylation along with dysregulation in the mechanisms of addition, elimination and maintenance of methyl groups in the DNA of ICM. We describe relevant alterations in the DNMT3B system, which promote a normal Dnmt3b function despite its upregulation.