Metabolic transcriptional memory

Abstract

Background: Organisms can be primed by metabolic exposures to continue expressing response genes even once the metabolite is no longer available, and can affect the speed and magnitude of responsive gene expression during subsequent exposures. This "metabolic transcriptional memory" can have a profound impact on the survivability of organisms in fluctuating environments.

Scope of review: Here I present several examples of metabolic transcriptional memory in the microbial world and discuss what is known so far regarding the underlying mechanisms, which mainly focus on chromatin modifications, protein inheritance, and broad changes in metabolic network. From these lessons learned in microbes, some insights into the yet understudied human metabolic memory can be gained. I thus discuss the implications of metabolic memory in disease progression in humans - i.e., the memory of high blood sugar exposure and the resulting effects on diabetic complications.

Major conclusions: Carbon source shifts from glucose to other less preferred sugars such as lactose, galactose, and maltose for energy metabolism as well as starvation of a signal transduction precursor sugar inositol are well-studied examples of metabolic transcriptional memory in Escherichia coli and Saccharomyces cerevisiae. Although the specific factors guiding metabolic transcriptional memory are not necessarily conserved from microbes to humans, the same basic mechanisms are in play, as is observed in hyperglycemic memory. Exploration of new metabolic transcriptional memory systems as well as further detailed mechanistic analyses of known memory contexts in microbes is therefore central to understanding metabolic memory in humans, and may be of relevance for the successful treatment of the ever-growing epidemic of diabetes.

Keywords: Bistability; Chromatin modification; Diabetes; Galactose; Glucose; Hyperglycemia; Hysteresis; Inositol; Lactose; Maltose; Metabolic memory; Metabolic network; Protein inheritance; Reinduction memory; Transcriptional memory.

Figure 1

Schematic representation of metabolic exposures inducing metabolic transcriptional memory. (A) Environmental stimuli induce changes to gene expression. Memory of metabolic exposures via a variety of mechanisms can result in changes to gene expression that persist even after the initiating stimulus has been removed. Metabolic transcriptional memory is often associated with positive feedback, resulting in exponential gene expression until reaching a steady state plateau. Depicted here is a memory component with a limited lifetime (scale may be minutes to generations) resulting from, for example, dilution by cell division and degradation, unless actively maintained to result in permanent gene expression changes. (B) Metabolic transcriptional memory can also result in adaptation such that subsequent stimuli induce changes in gene expression with an altered rate or strength in comparison to the initial exposure. (C and D) Factors that cause loss of memory have been discovered in several metabolic transcriptional memory systems and have provided insight into the mechanisms of metabolic memory. Further large-scale screens are needed to identify more loss of memory factors (green) and to search for speculative gain of memory factors (red).

Figure 2

Various mechanisms underlie metabolic transcriptional memory. (A) Chromatin modifications, proteins, and metabolic network have all been described as contributors to metabolic transcriptional memory, and can work in concert to widen memory parameters and potential.

Figure 3

Hysteresis often emerges from bistability and bimodality. (A) Gene activation processes with various kinds of feedback (shown here is an example of positive feedback) are associated with bistability, such that at certain inducer concentrations and gene induction times, stochastic mechanisms cause some cells in the population to turn on and rapidly produce an expression product (green). This results in a bimodal distribution of gene expression, with induced cells having hundreds-to thousands-fold of product in comparison to uninduced cells. To observe bimodal gene expression, single-cell measurements are necessary, such as by time-resolved imaging or flow cytometry analysis. Bistable gene expression is often associated with hysteresis, where the threshold concentration of a pathway component to turn a gene on is higher than to turn it off due to, for example, a positive-feedback process in the gene activation pathway.

Figure 4

Microbial metabolic transcriptional memory mechanisms. (A) Lactose metabolism and lac operon hysteresis in E. coli. The lac operon consists of lacZ, lacY, and lacA, which are responsible for the uptake and metabolism of lactose. The LacI repressor maintains the operon in an inactive state when glucose available. Under inducing conditions, lactose uptake is followed by conversion to allolactose, which binds to and causes release of the repressor, allowing for the lac operon to be expressed. This results in a positive feedback of the LacY permease and metabolizing enzymes LacZ and LacA, even when inducer concentrations fall below the initial threshold for induction, resulting in hysteresis. (B) Galactose metabolism and GAL reinduction memory in S. cerevisiae. Under repression, Gal4 activator bound at GAL promoters (GAL1, GAL2, GAL7, and GAL10) is repressed by Gal80. In the presence of galactose, intracellular galactose binds to Gal3, which then binds and removes the Gal80 repressor, allowing the GAL genes to be expressed. GAL1 anchors to the nuclear periphery by the nuclear pore complex (NPC) and forms an intragene loop. GAL reinduction memory is accomplished by a combination of chromatin modifications and protein inheritance, including expression of respiratory metabolism proteins (RMPs) and Gal1 during initial induction, which remain during the memory state. RMPs accelerate the transition back to respiration and Gal1 can function like Gal3 to relieve Gal80 repression during reinduction. The GAL1 intragene loop can be maintained during memory to also facilitate reinduction. Tup1-dependent H2A.Z incorporation during memory possibly also promotes reinduction, by forming a less stable nucleosome. Chromatin remodeling by the SWI/SNF remodeling complex and Set1-mediated histone H3 lysine 4 trimethylation (H3K4me3) are important factors involved in GAL gene expression, and have also been implicated in GAL metabolic transcriptional memory. (C) Maltose metabolism and MAL gene reinduction memory. Maltose metabolism involves a transporter MalT, a maltase MalS, and a transcriptional activator MalR that induces MalT and MalS that are expressed in the presence of maltose. Growth in maltose results in a change towards respiration, resulting in expression of respiratory metabolism proteins (RMPs) that precedes MAL gene expression and metabolism. These RMPs can persist during the memory state, and facilitate MAL reinduction memory by promoting the shift back to the respiratory state. (D) Inositol starvation and INO1 reinduction memory. During inositol starvation, Ino1 is expressed to synthesize inositol. Reinduction of INO1 is actually lower than the initial induction; however localization to the nuclear pore complex (NPC) during the initial induction is maintained during memory, and promotes reinduction. Thus although INO1 metabolic transcriptional memory results in lower Ino1 expression, nuclear localization in combination with chromatin modifications including incorporation of H2A.Z and H3K4me2 during the memory state cooperate to permit Ino1 expression during reinduction.

Figure 5

Metabolic memory of hyperglycemia is accomplished via a combination of mechanisms. (A) Chromatin modifications such as decreased DNA methylation, increased histone acetylation, and changes in histone methylation as well as microRNAs (miRNAs) contribute to hyperglycemic memory. In addition, an increase in reactive oxygen species (ROS) leads to oxidative stress, and an increase in NF-κB leads to pro-inflammatory signaling and chronic inflammation. Overexposure to sugar leads to formation of advanced glycation end products (AGEs) that affect protein structure and function. Glycolytic genes are induced along with reduced binding of PPAR-γ to chromatin of genes inhibiting glycolysis, resulting in persistently upregulated NADH. These various factors together lead to metabolic dysregulation and insulin resistance, leading to diabetic complications such as vascular disease, endothelial dysfunction, and adipocyte dysregulation.