Metabolism as a central regulator of β‐cell chromatin state

Abstract

Pancreatic b-cells are critical mediators of glucose homeostasis in the body, and proper cellular nutrient metabolism is critical to b-cell function. Several interacting signaling networks that uniquely control b-cell metabolism produce essential substrates and co-factors for catalytic reactions, including reactions that modify chromatin. Chromatin modifications, in turn, regulate gene expression. The reactions that modify chromatin are therefore well-positioned to adjust gene expression programs according to nutrient availability. It follows that dysregulation of nutrient metabolism in b-cells may impact chromatin state and gene expression through altering the availability of these substrates and co-factors. Metabolic disorders such as type 2 diabetes (T2D) can significantly alter metabolite levels in cells. This suggests that a driver of b-cell dysfunction during T2D may be the altered availability of substrates or co-factors necessary to maintain b-cell chromatin state. Induced changes in the b-cell chromatin modifications may then lead to dysregulation of gene expression, in turn contributing to the downward cascade of events that leads to the loss of functional b-cell mass, and loss of glucose homeostasis, that occurs in T2D.

Harnessing conserved signaling and metabolic pathways to enhance the maturation of functional engineered tissues

“…Upstream of ERRγ, AMPK is implicated in both the development and functional maturation of the pancreas 143 . The Akt/AMPK balance, previously discussed, seems to hold constant in β-cells, with high mTORC1 activity often opposing metabolic specialization (e.g., the oxidative switch) and islet function (glucose regulation) in vivo 144 ; the precise role of AMPK in insulinar activity remains unclear 145 , but is likely to be involved in functional maintenance, as well as pathophysiological progression, through its downstream effectors and their transcriptional regulation 146 . Several circulating hormones are likely to influence pancreatic maturation; hydrocortisone increases the expression of insulin, as well as the glucose-sensing molecules that stimulate its release 147 .…”

Epigenetics, microRNA and Metabolic Syndrome: A Comprehensive Review

“…Among these modifications, chromatin structures have been associated with the biogenesis and post-transcriptional regulation of miRNAs [ 82 ]. Several miRNAs related to metabolism are shown to be regulated by a repressive chromatin structure involving H3K27me3 mediated by an epigenetic regulator enhancer of zester homolog 2 (EZH2) [ 83 , 84 ]. Expression of miR-101-3p, a pancreatic islet-enriched miRNA with a role in insulin secretion and β cell functioning [ 85 ], is demonstrated to be regulated by H3K27me3 modification in EZH2.…”

DNA Methylation Patterning and the Regulation of Beta Cell Homeostasis

“…Of note, S-adenosyl homocysteine (SAH), the byproduct of SAM utilization during the methylation reaction, is an inhibitor of DNA methylation (121). Importantly, the levels of SAH are elevated in obesity (122,123), and can contribute to aberrant DNA methylation in the offspring in response to maternal obesity. Therefore, nutritional imbalances during fetal or neonatal life can alter the epigenetic program responsible for the development, growth, and function of metabolic organs, thus predisposing the offspring to diabetes (14,124).…”