Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells.

Aneta M Dobosz,Ewelina Lipiec,Agnieszka Dobrzyn,Justyna Janikiewicz,Pawel Dobrzyn,Anna M Borkowska,Wojciech M Kwiatek,Anna Dziewulska

doi:10.3390/ijms21186844

Abstract

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.

Highlights

The emergence of type 2 diabetes (T2D) as a global pandemic is a major issue
The level of global DNA methylation in pancreatic islets that were isolated from Stearoyl-CoA desaturase 1 (SCD1)−/− mice significantly decreased by 40% compared with WT islets (Figure 1A)
GDNA methylation levels in SCD1-deficient INS-1E cells that were incubated with palmitate decreased by nearly 60% compared with controls and were higher than in cells that were treated with the SCD1 inhibitor, or siRNA against SCD1 alone (Figure 1D,E)

Summary

Introduction

The emergence of type 2 diabetes (T2D) as a global pandemic is a major issue. The two central abnormalities that characterize the pathophysiology of T2D are insulin resistance in peripheral tissues and the progressive loss of β-cell function in pancreatic islets [1,2,3]. DNA methylation is a chemical post-replicative modification whereby a methyl group (-CH3) is covalently added to the fifth carbon of the cytosine ring of 5 -to-3 -oriented CG dinucleotides, which are known as CpG sites [4]. Cytosine methylation within the promoter region is known to inversely correlate with expression of the gene by affecting the binding of transcription factors and methylcytosine-binding proteins to the DNA and heterochromatin formation [5]. DNA methylation patterns are generated and maintained by a family of DNA methyltransferases (DNMTs) This process is highly dependent on the availability of S-adenosyl methionine (SAM), a primary methyl group donor [6]. DNMT1 activity and protein stability are highly regulated by various post-translational modifications, such as acetylation, methylation, and ubiquitination—through interactions with other epigenetic effectors, such as the NAD-dependent deacetylase sirtuin-1 (SIRT1) [9,10]

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Results

Conclusion