Stearoyl-CoA desaturase 1 activity determines the maintenance of DNMT1-mediated DNA methylation patterns in pancreatic β\beta-Cells

Metabolic stress, such as lipotoxicity, affects the DNA methylation profile in pancreatic β-cells and thus contributes to β-cell failure and the progression of type 2 diabetes (T2D). Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme that is involved in monounsaturated fatty acid synthesis, which protects pancreatic β-cells against lipotoxicity. The present study found that SCD1 is also required for the establishment and maintenance of DNA methylation patterns in β-cells. We showed that SCD1 inhibition/deficiency caused DNA hypomethylation and changed the methyl group distribution within chromosomes in β-cells. Lower levels of DNA methylation in SCD1-deficient β-cells were followed by lower levels of DNA methyltransferase 1 (DNMT1). We also found that the downregulation of SCD1 in pancreatic β-cells led to the activation of adenosine monophosphate-activated protein kinase (AMPK) and an increase in the activity of the NAD-dependent deacetylase sirtuin-1 (SIRT1). Furthermore, the physical association between DNMT1 and SIRT1 stimulated the deacetylation of DNMT1 under conditions of SCD1 inhibition/downregulation, suggesting a mechanism by which SCD1 exerts control over DNMT1. We also found that SCD1-deficient β-cells that were treated with compound c, an inhibitor of AMPK, were characterized by higher levels of both global DNA methylation and DNMT1 protein expression compared with untreated cells. Therefore, we found that activation of the AMPK/SIRT1 signaling pathway mediates the effect of SCD1 inhibition/deficiency on DNA methylation status in pancreatic β-cells. Altogether, these findings suggest that SCD1 is a gatekeeper that protects β-cells against the lipid-derived loss of DNA methylation and provide mechanistic insights into the mechanism by which SCD1 regulates DNA methylation patterns in β-cells and T2D-relevant tissues

High-Throughput Approaches onto Uncover (Epi)Genomic Architecture of Type 2 Diabetes

Type 2 diabetes (T2D) is a complex disorder that is caused by a combination of genetic, epigenetic, and environmental factors. High-throughput approaches have opened a new avenue toward a better understanding of the molecular bases of T2D. A genome-wide association studies (GWASs) identified a group of the most common susceptibility genes for T2D (i.e., TCF7L2, PPARG, KCNJ1, HNF1A, PTPN1, and CDKAL1) and illuminated novel disease-causing pathways. Next-generation sequencing (NGS)-based techniques have shed light on rare-coding genetic variants that account for an appreciable fraction of T2D heritability (KCNQ1 and ADRA2A) and population risk of T2D (SLC16A11, TPCN2, PAM, and CCND2). Moreover, single-cell sequencing of human pancreatic islets identified gene signatures that are exclusive to α-cells (GCG, IRX2, and IGFBP2) and β-cells (INS, ADCYAP1, INS-IGF2, and MAFA). Ongoing epigenome-wide association studies (EWASs) have progressively defined links between epigenetic markers and the transcriptional activity of T2D target genes. Differentially methylated regions were found in TCF7L2, THADA, KCNQ1, TXNIP, SOCS3, SREBF1, and KLF14 loci that are related to T2D. Additionally, chromatin state maps in pancreatic islets were provided and several non-coding RNAs (ncRNA) that are key to T2D pathogenesis were identified (i.e., miR-375). The present review summarizes major progress that has been made in mapping the (epi)genomic landscape of T2D within the last few years

The Effects of Vitamin D on the Expression of IL-33 and Its Receptor ST2 in Skin Cells; Potential Implication for Psoriasis

Interleukin 33 (IL-33) belongs to the IL-1 family and is produced constitutively by epithelial and endothelial cells of various organs, such as the skin. It takes part in the maintenance of tissue homeostasis, repair, and immune response, including activation of Th2 lymphocytes. Its involvement in pathogenesis of several inflammatory diseases including psoriasis was also suggested, but this is not fully understood. The aim of the study was to investigate expression of IL-33 and its receptor, ST2, in psoriasis, and the effects of the active form of vitamin D (1,25(OH)2D3) on their expression in skin cells. Here we examined mRNA and protein profiles of IL-33 and ST2 in 18 psoriatic patients and healthy volunteers by qPCR and immunostaining techniques. Potential effects of 1,25(OH)2D3 and its receptor (VDR) on the expression of IL-33 and ST2 were tested in cultured keratinocytes, melanocytes, fibroblasts, and basal cell carcinoma cells. It was shown that 1,25(OH)2D3 effectively stimulated expression of IL-33 and its receptor ST2’s mRNAs in a time-dependent manner, in keratinocytes and to the lesser extends in melanocytes, but not in fibroblasts. Furthermore, the effect of vitamin D on expression of IL-33 and ST2 was VDR-dependent. Finally, we demonstrated that the expression of mRNA for IL-33 was mainly elevated in the psoriatic skin but not in its margin. Interestingly, ST2 mRNA was downregulated in psoriatic lesion compared to both marginal tissue as well as healthy skin. Our data indicated that vitamin D can modulate IL-33 signaling, opening up new perspectives for our understanding of the mechanism of vitamin D action in psoriasis therapy

Breast cancer chemotherapy induces vascular dysfunction and hypertension through NOX4 dependent mechanism

Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets. We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin and cyclophosphamide (NACT), and women with no history of such treatment matched for key clinical parameters. Mechanisms were explored in wild-type and Nox4-/- mice and human microvascular endothelial cells. Endothelium-dependent vasodilatation is severely impaired in patients after NACT, while endothelium-independent responses remain normal. This was mimicked by 24-hour exposure of arteries to NACT agents ex-vivo. When applied individually, only docetaxel impaired endothelial function in human vessels. Mechanistic studies showed that NACT increased inhibitory eNOS phosphorylation of threonine 495 in a ROCK-dependent manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. NOX4 increase in human arteries may be mediated epigenetically by diminished DNA methylation of the NOX4 promoter. Docetaxel induced endothelial dysfunction and hypertension in mice. These were prevented in Nox4-/- and by pharmacological inhibition of Nox4 or Rock. Commonly used chemotherapeutic agents, and in particular, docetaxel, alter vascular function by promoting inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases