Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes

Abstract

Diabetic patients continue to develop inflammation and vascular complications even after achieving glycemic control. This poorly understood ''metabolic memory'' phenomenon poses major challenges in treating diabetes. Recent studies demonstrate a link between epigenetic changes such as chromatin histone lysine methylation and gene expression. We hypothesized that H3 lysine-9 tri-methylation (H3K9me3), a key repressive and relatively stable epigenetic chromatin mark, may be involved in metabolic memory. This was tested in vascular smooth muscle cells (VSMC) derived from type 2 diabetic db/db mice. These cells exhibit a persistent atherogenic and inflammatory phenotype even after culture in vitro. ChIP assays showed that H3K9me3 levels were significantly decreased at the promoters of key inflammatory genes in cultured db/db VSMC relative to control db/؉ cells. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase Suv39h1 were also reduced in db/db VSMC. Furthermore, db/db VSMC were hypersensitive to TNF-␣ inflammatory stimulus, which induced dramatic and sustained decreases in promoter H3K9me3 and Suv39h1 occupancy. Recruitment of corepressor HP1␣ was also reduced under these conditions in db/db cells. Overexpression of SUV39H1 in db/db VSMC reversed this diabetic phenotype. Conversely, gene silencing of SUV39H1 with shRNAs in normal human VSMC (HVSMC) increased inflammatory genes. HVSMC cultured in high glucose also showed increased inflammatory gene expression and decreased H3K9me3 at their promoters. These results demonstrate protective roles for H3K9me3 and Suv39h1 against the preactivated state of diabetic VSMC. Dysregulation of epigenetic histone modifications may be a major underlying mechanism for metabolic memory and sustained proinflammatory phenotype of diabetic cells.

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

“…Numerous enzymes associated with H3K9me3, the mark associated with heterochromatin, including acetyltransferases (SRC‐1/ Ncoa1 ), deacetylases (Hdac3), methyltransferases (Suv39 h1 and G9a/ Ehmt2 ), and demethylases (Jhmdh2a/Kdm3a, Jmjd2c/Kdm4c), have been linked to fatty liver, diabetes, and obesity (Picard et al., 2002; Sun et al., 2012; Tateishi et al., 2009; Wang et al., 2013). In addition, levels of H3K9me3 increase during caloric restriction and decrease in db/db mice and other models of hyperglycemia (Vaquero & Reinberg, 2009; Villeneuve et al., 2008). Together, these studies underscore the importance of investigating how dysregulation of heterochromatin at the nuclear lamina leads to metabolic dysfunction.…”

“…Additionally, LMNA mutations lead to partial lipodystrophy, a condition associated with insulin‐resistant diabetes, hypertriglyceridemia, and hepatic steatosis (Shackleton et al., 2000). Multiple enzymes modulating covalent modifications to lysine 9 of histone 3 (H3K9), the mark associated with heterochromatin in lamina‐associated domains (Guelen et al., 2008), have been linked to fatty liver, hyperlipidemia, diabetes, and obesity (Picard et al., 2002; Sun et al., 2012; Tateishi, Okada, Kallin & Zhang, 2009; Villeneuve et al., 2008; Wang et al., 2013). We have recently implicated lamina‐associated factors Hdac3 and Srf in age‐dependent dysregulation of lipid metabolism in the liver (Bochkis, Przybylski, Chen & Regev, 2014).…”

Epigenetic changes in renal genes dysregulated in mouse and rat models of type 1 diabetes

“…Chromatin modifications may have an important role during the initiation and progression of diabetic nephropathy (DN) [1][2][3][4][5][6][7][8][9][10][11] by altering the expression of genes involved in this disease. Pioneering work by Natarajan and coworkers 2,11 has suggested alterations in epigenetic control of inflammatory gene responses in the cardiovascular system (CVS).…”

High-phosphate-induced calcification is related to SM22α promoter methylation in vascular smooth muscle cells

“…(19) Epigenetic response of VSMCs to environmental conditions through increased methylation has been reported previously. (20) Moreover, hypermethylation of target genes, such as the estrogen receptor a gene promoter, has been shown to influence transition of VSMCs from contractile to proliferative phenotype. (21,22) An interesting feature that would require additional investigation is the selectivity of high phosphate when inducing methylation of specific genes.…”