SIRT1/2 orchestrate acquisition of DNA methylation and loss of histone H3 activating marks to prevent premature activation of inflammatory genes in macrophages

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.

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

“…SIRT1 and SIRT2 are rapidly activated during macrophage differentiation, and their inhibition results in the upregulation of many inflammation-related genes. SIRT1 and SIRT2 interact with DNMT3B and bind to the promoters of genes that become hypermethylated during macrophage differentiation that was shown in human macrophages in vitro [161]. IL-4-activated STAT6 acts as a transcriptional repressor in an HDAC3-dependent manner in BMDMs [189].…”

Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment

“… 109 , 110 Here, we discuss one study that demonstrated a novel role for SIRT1/2 in regulation coupled with DNA methylation via DNMT3B during macrophage differentiation. 111 SIRT1/2 were significantly upregulated during macrophage differentiation. The authors then discovered that SIRT1/2 mediated gains of methylation accompanied by decreases in activating histone marks at inflammatory loci in genes, such as ADORA2A , RUNX3 , and JAK , which resulted in general gene repression.…”

<p>ADAMDEC1 and Its Role in Inflammatory Disease and Cancer</p>

“…Differentiation of peripheral blood-derived monocytes into macrophages in vitro by various stimuli, such as human serum, 1α-25dihydroxyvitamin D3 or macrophage colony-stimulating factor (MCSF) led to induced expression of ADAMDEC1. 17,21 An additional increase in the level of ADAMDEC1 was seen when the MDMs were stimulated with lipopolysaccharides (LPS), which is present in the lamina propria of the healthy intestine. 17,22 Sirtuins 1 and 2 (SIRT1/2), two NAD-dependent deacetylases, were purported to be responsible for de-methylation and elevation in ADAMDEC1 expression in the LPS-stimulated macrophages.…”

“…17,22 Sirtuins 1 and 2 (SIRT1/2), two NAD-dependent deacetylases, were purported to be responsible for de-methylation and elevation in ADAMDEC1 expression in the LPS-stimulated macrophages. 21 More recently, a number of transcriptomic studies have also identified ADAMDEC1 expression in a range of MDM phenotypes in vitro. [23][24][25][26][27][28][29] The consensus from these in vitro studies is that the ADAMDEC1 expression and secretion seem to be induced upon monocyte to macrophage differentiation irrespective of the final macrophage phenotype.…”