Epigenetic mechanisms contributing to excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) in pulmonary arterial hypertension (PAH) include: i) DNA methylation via DNA methyltransferases (DNMTs
); ii) histone modifications, mainly methylation and acetylation, regulated by histone acetyltransferases (HATs) histone methyltransfereses (HMTs), histone deacetylases (HDACs), and histone demethylases (HDMs).
Given the observed link between DNMTs
enzyme activity and regulation of the epigenome, an attempt was made to examine whether dietary PUFA could modulate global DNA methylation in selected rat tissues.
(22) This event is catalyzed and maintained by DNMTs
Chemicals could have a direct impact on the activity of epigenetic modification enzymes (HDACS, DNMTs
, etc.), could block enzymes (such as DNMT
) from accessing DNA by activating transcription factors that bind DNA, or both.
En mamiferos, la unica modificacion epigenetica de la molecula de DNA es producida por la adicion covalente de un grupo CH3 de SAMe, a la posicion 5 del nucleotido de citosina del dinucleotido CpG, en una reaccion catalizada por DNMTs
. Posterior a la donacion del grupo CH3, SAMe se convierte en S-adenosilhomocisteina (SAH).
DNA methylation by DNMTs
has a repressive action on chromatin, similar to that of miR-let-7 family members.
Oxidative stress can eliminate or induce specific DNA and histone methylation by regulating corresponding enzymes such as DNMTs
and ten-eleven translocations (TETs); elaborate details are reviewed by Ito et al.
inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), and inhibitors of the bromodomain and extraterminal motif proteins (iBET), approved by the US Food and Drug Administration (FDA), are actually in clinical trials for several malignancies and they are reviewed in detail in .
In systemic sclerosis (SSc), a rare connective tissue disease characterized by chronic inflammation and fibrosis with deleterious effect in the kidney, DNA hypomethylation in [CD4.sup.+] Tlymphocytes from SSc patients decreased the expression of methylation genes such as DNA methyltransferases (DNMT
)1 and methyl-CpG-binding domain proteins (MBD)3 and MBD4 [46, 47].
factors help to moderate the action of DNMTs
HP1-encoding protein induces heterochromatin formation and interacts with histones and DNMTs
with the main function of silencing gene transcription [33, 35, 44].
Any type of IM approach that directly exerts an effect on epigenetic enzymes such as DNA methyltransferases (DNMTs
), histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs), and histone demethylases (HDMs) such that there is an altered bioavailability of these enzymes in the cell is said to follow Type 1 direct pathway.