Liver histone H3 methylation and acetylation may associate with type 2 diabetes development

Abstract

Type 2 diabetes (T2D) is a complicated systemic disease, and the exact pathogenetic molecular mechanism is unclear. Distinct histone modifications regulate gene expression in certain diseases, but little is known about histone epigenetics in diabetes. In the current study, C57BL/6 J mice were used to build T2D model, then treated with exendin-4 (10 μg/kg). Histone H3K9 and H3K23 acetylation, H3K4 monomethylation and H3K9 dimethylation were explored by Western blotting of liver histone extracts. Real-time polymerase chain reaction (PCR) was used to examine expression levels of diabetes-related genes, while chromatin immunoprecipitation (ChIP) was applied to analyze H3 and H3K9 acetylation, H3K4 monomethylation, and H3K9 dimethylation in the promoter of facilitated glucose transporter member 2 (Glut2) gene. The results showed that liver's total H3K4 monomethylation and H3K9 dimethylation was increased in diabetic mice, which was abrogated with the treatment of exendin-4. In contrast, H3K9 and H3K23 acetylation were reduced in diabetic mice, while exendin-4 only alleviated the reduction of H3K9 acetylation. Our data indicated that the progression of type 2 diabetes mellitus (T2D) is associated with global liver histone H3K9 and H3K23 acetylation, H3K4 monomethylation, and H3K9 dimethylation. Exploiting exact histone modify enzyme inhibitors, which may represent a novel strategy to prevent T2D.

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

“…It has been reported that high glucose alters the gene expression by methylation or acetylation of lysine residues on histone H3. A recent report showed the involvement of H3K36me2, H3K27me3, H3K9me2, and H3K23ac in metabolic disorder . We also show that there is increased K36 di‐methylation of histone H3 in HFD + low dose STZ‐induced diabetic conditions and this elevation was suppressed by l ‐Met‐S as well as metformin treatment.…”

“…The activity of DNMT1 is tightly regulated by metabolites of l ‐Met; SAH and SAM, exclusively . Posttranslational histone modifications such as acetylation, methylation, phosphorylation, sumoylation, or ubiquitination also affect the expression of various genes associated with autoimmunity, carcinogenesis, and diabetes . Recent studies have shown an increase in global H3K4 monomethylation, H3K9 dimethylation, and H3K36 dimethylation in the liver tissue under diabetic conditions .…”

Involvement of Reversible Protein Methylation in 13-Lined Ground Squirrel Hibernation.

“…The fact that H3K4me levels are upregulated during torpor does seem contradictory to the hibernator's need to preserve cellular resources in these times, although increases in H3K4me may be signaling the cell's need for transcription of torpor-specific proteins under the control of H3K4me-mediated transcriptional activation. Studies investigating the role of H3K4 methylation within the liver in the context of human diabetes and obesity have shown that levels of H3K4me are enhanced in diabetic conditions, and that the effect may be attenuated through treatment with glucagon-agonists (Muka et al, 2016;Tu et al, 2015). Given that hibernating mammals are reliant on lipid catabolism during torpor, as well as aberrant endocrine signaling which mirrors that seen in diabetes (Bauman et al, 1987;Wu et al, 2013), a similar mechanism may be utilized by the liver to accommodate shifts in metabolic fuel selection through increased levels of H3K4me.…”

“…Interactions between methylated H3K4 and repressive methyl modifications on H3K9, which is decreased during both torpor and arousal within liver, may be possible given observations of histone cross-talk between the two modifications (Chaturvedi et al, 2012;Nightingale et al, 2007). It would appear that by enhancing levels of activating histone modifications during torpor and arousal the genome may be poised for rapid shifts in protein synthesis activity, required to provide metabolic resources to the body's organs during arousal (Hindle et al, 2014;Miao et al, 2007;Serkova et al, 2007;Tu et al, 2015). The methylation status of H3K36me 2 was also investigated, and shown to be heightened in both skeletal muscle and liver, in LA in the former tissue, but throughout torpor and arousal in the latter tissue.…”

“…The multitude of changes in gene expression and enzymatic activity that occur in the liver rely on the work of several endocrine regulators and therefore has parallels to the human condition, type 2 diabetes (Carey et al, 2003;Klug and Brigham, 2015;Wu et al, 2013). Interestingly, the methylation status of histone H3 was shown to be effected in a mouse model of type 2 diabetes, wherein levels of H3K4me and H3K9me 2 were increased and this effect could be rescued following treatment with an insulin-secretion stimulator (Tu et al, 2015). It has not currently been shown whether or not this shift requires the influence of differential PTMs on histone proteins, although given the ability of histone modifications to discriminate and regulate the abundance of specific proteins over time-scales of hours to days, it stands to reason that this mechanism may also regulate physiological changes taking place within the liver (Keating and El-Osta, 2015;Tian and Xu, 2015).…”