Abstract

Sirtuins 1 and 2 (SIRT1/2) are two NAD-dependent deacetylases with major roles in inflammation. In addition to deacetylating histones and other proteins, SIRT1/2-mediated regulation is coupled with other epigenetic enzymes. Here, we investigate the links between SIRT1/2 activity and DNA methylation in macrophage differentiation due to their relevance in myeloid cells. SIRT1/2 display drastic upregulation during macrophage differentiation and their inhibition impacts the expression of many inflammation-related genes. In this context, SIRT1/2 inhibition abrogates DNA methylation gains, but does not affect demethylation. Inhibition of hypermethylation occurs at many inflammatory loci, which results in more drastic upregulation of their expression upon macrophage polarization following bacterial lipopolysaccharide (LPS) challenge. SIRT1/2-mediated gains of methylation concur with decreases in activating histone marks, and their inhibition revert these histone marks to resemble an open chromatin. Remarkably, specific inhibition of DNA methyltransferases is sufficient to upregulate inflammatory genes that are maintained in a silent state by SIRT1/2. Both SIRT1 and SIRT2 directly interact with DNMT3B, and their binding to proinflammatory genes is lost upon exposure to LPS or through pharmacological inhibition of their activity. In all, we describe a novel role for SIRT1/2 to restrict premature activation of proinflammatory genes.

Highlights

  • Macrophages (MACs) are required to respond to a wide range of environmental stimuli which specify their functions

  • We studied the effects of Sirtuins 1 and 2 (SIRT1/2) inhibition on global gene expression, DNA methylation and changes in various histone marks during macrophage differentiation and activation

  • SIRT1/2 become rapidly upregulated during macrophage differentiation and their inhibition upregulates many inflammation-related genes

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Summary

Introduction

Macrophages (MACs) are required to respond to a wide range of environmental stimuli which specify their functions. In order to acquire the corresponding phenotypes of each cell type, MACs undergo very specific changes in gene expression that are mediated by the complex interplay between signalling, transcriptional and epigenetic machineries. Deregulation of these processes results in abnormal MAC function which forms the basis for many immune diseases. Highly conserved proteins that belong to the family of class III histone deacetylases, are key regulators of transcriptional and epigenetic landscape. This family of proteins has been implicated in a wide range of biological and pathological processes, including metabolism, aging and inflammation.

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