The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by ß-Glucan.

Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and transcriptional reprogramming. Because of its previous associations with metabolic and transcriptional memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesize that the Set7 methyltransferase has an important role in trained immunity induced by ß-glucan. Using pharmacological studies of human primary monocytes, we identify trained immunity-specific immunometabolic pathways regulated by Set7, including a previously unreported H3K4me1-dependent plasticity in the induction of oxidative phosphorylation. Recapitulation of ß-glucan training in vivo additionally identifies Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as a key regulator of trained immunity, these findings provide mechanistic insight into sustained metabolic changes and underscore the importance of characterizing regulatory circuits of innate immune memory.

RNA-seq-based identification of Star upregulation by islet amyloid formation.

Aggregation of islet amyloid polypeptide (IAPP) into islet amyloid results in ß-cell toxicity in human type 2 diabetes. To determine the effect of islet amyloid formation on gene expression, we performed ribonucleic acid (RNA) sequencing (RNA-seq) analysis using cultured islets from either wild-type mice (mIAPP), which are not amyloid prone, or mice that express human IAPP (hIAPP), which develop amyloid. Comparing mIAPP and hIAPP islets, 5025 genes were differentially regulated (2439 upregulated and 2586 downregulated). When considering gene sets (reactomes), 248 and 52 pathways were up- and downregulated, respectively. Of the top 100 genes upregulated under two conditions of amyloid formation, seven were common. Of these seven genes, only steroidogenic acute regulatory protein (Star) demonstrated no effect of glucose per se to modify its expression. We confirmed this differential gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and also demonstrated the presence of STAR protein in islets containing amyloid. Furthermore, Star is a part of reactomes representing metabolism, metabolism of lipids, metabolism of steroid hormones, metabolism of steroids and pregnenolone biosynthesis. Thus, examining gene expression that is differentially regulated by islet amyloid has the ability to identify new molecules involved in islet physiology and pathology applicable to type 2 diabetes.

Epigenetic Contribution to the Development and Progression of Vascular Diabetic Complications.

SIGNIFICANCE: The number of people suffering from diabetes worldwide is steadily rising. Complications from diabetes, including cardiovascular and renal disease, contribute to the high morbidity and mortality associated with this disease. Recent Advances: Hyperglycemia promotes tissue damage through diverse mechanisms involving increased production of reactive oxygen species. Increased oxidative stress drives changes in chromatin structure that mediate gene expression changes leading to the upregulation of proinflammatory and profibrotic mediators. The epigenetic contribution to diabetes-induced changes in gene expression is increasingly recognized as a key factor in the development and progression of vascular diabetic complications. CRITICAL ISSUES: The mechanisms through which stimuli from the diabetic milieu promote epigenetic changes remain poorly understood. In addition, glycemic control constitutes an important factor influencing epigenetic states in diabetes, and the phenomenon of hyperglycemic memory warrants further research. FUTURE DIRECTIONS: Knowledge of the molecular mechanisms underlying epigenetic changes in diabetes may allow the design of novel therapeutic strategies to reduce the burden of diabetic complications. Furthermore, certain epigenetic markers are detected early during the onset of diabetes and its complications and may prove useful as biomarkers for disease risk prediction.

Metabolism and chromatin dynamics in health and disease.

The regulation of gene expression in response to environmental and behavioural cues is critical for many biological processes. Histone tail modifications are dynamic and, as such, can regulate gene expression in response to extracellular conditions. Many of the enzymes involved in adding and removing these modifications require cofactors that are products of intermediary metabolism pathways, thus linking cellular metabolism to the regulation of gene expression. Furthermore, the expression and activity of such enzymes are influenced by the cellular concentrations of metabolic products. Under- and over-nutrition can induce epigenetic changes that influence chromatin structure and define a metabolic program. Importantly, recent studies have demonstrated that such changes during the pre- and peri-natal periods can be long-lasting, influencing the disease risk later in life and could be transmitted to subsequent generations. Moreover, damaging gene expression patterns observed in metabolic diseases such as diabetes are driven by persistent changes in chromatin structure, raising the possibility of targeting epigenetic pathways for the treatment of disease.