Metabolic Transcriptional Regulation Research Articles

Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma.

Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate the metabolic consequences of uniporter loss- and gain-of-function, and identify a key transcriptional regulator that mediates these effects. Using gene expression profiling and proteomic, we find that loss of uniporter function increases the expression of proteins in the branched-chain amino acid (BCAA) catabolism pathway. Activity is further augmented through phosphorylation of the enzyme that catalyzes this pathway's committed step. Conversely, in the liver cancer fibrolamellar carcinoma (FLC)-which we demonstrate to have high mitochondrial calcium levels- expression of BCAA catabolism enzymes is suppressed. We also observe uniporter-dependent suppression of the transcription factor KLF15, a master regulator of liver metabolic gene expression, including those involved in BCAA catabolism. Notably, loss of uniporter activity upregulates KLF15, along with its transcriptional target ornithine transcarbamylase (OTC), a component of the urea cycle, suggesting that uniporter hyperactivation may contribute to the hyperammonemia observed in FLC patients. Collectively, we establish that FLC has increased mitochondrial calcium levels, and identify an important role for mitochondrial calcium signaling in metabolic adaptation through the transcriptional regulation of metabolism.

Transcriptional regulation of metabolism in the intestinal epithelium.

Epithelial metabolism in the intestine is increasingly known to be important for stem cell maintenance and activity while also affecting weight gain and diseases. This review compiles studies from recent years which describe major transcription factors controlling metabolic activity across the intestinal epithelium as well as transcriptional and epigenetic networks controlling the factors themselves. Recent studies show that transcriptional regulators serve as the link between signals from the microbiota and diet and epithelial metabolism. Studies have advanced this paradigm to identify druggable targets to block weight gain or disease progression in mice. As such, there is great potential that a better understanding of these regulatory networks will improve our knowledge of intestinal physiology and promote discoveries to benefit human health.

The transcriptional regulator KLF15 is necessary for myoblast differentiation and muscle regeneration by activating FKBP5

Successful muscle regeneration following injury is essential for functional homeostasis of skeletal muscles. Krüppel-like factor 15 (KLF15) is a metabolic transcriptional regulator in the muscles. However, little is known regarding its function in muscle regeneration. Here, we examined microarray datasets from the Gene Expression Omnibus database, which indicated downregulated KLF15 in muscles from patients with various muscle diseases. Additionally, we found that Klf15 knockout (Klf15KO) impaired muscle regeneration following injury in mice. Furthermore, KLF15 expression was robustly induced during myoblast differentiation. Myoblasts with KLF15 deficiency showed a marked reduction in their fusion capacity. Unbiased transcriptome analysis of muscles on day 7 postinjury revealed downregulated genes involved in cell differentiation and metabolic processes in Klf15KO muscles. The FK506-binding protein 51 (FKBP5), a positive regulator of myoblast differentiation, was ranked as one of the most strongly downregulated genes in the Klf15KO group. A mechanistic search revealed that KLF15 binds directly to the promoter region of FKBP5 and activates FKBP5 expression. Local delivery of FKBP5 rescued the impaired muscle regeneration in Klf15KO mice. Our findings reveal a positive regulatory role of KLF15 in myoblast differentiation and muscle regeneration by activating FKBP5 expression. KLF15 signaling may be a novel therapeutic target for muscle disorders associated with injuries or diseases.

Low dissolved oxygen supply functions as a global regulator of the growth and metabolism of Aurantiochytrium sp. PKU#Mn16 in the early stages of docosahexaenoic acid fermentation

BackgroundThraustochytrids accumulate lipids with a high content of docosahexaenoic acid (DHA). Although their growth and DHA content are significantly affected by the dissolved oxygen (DO) supply, the role of DO on the transcriptional regulation of metabolism and accumulation of intracellular metabolites remains poorly understood. Here we investigate the effects of three different DO supply conditions (10%, 30%, and 50%) on the fed-batch culture of the Aurantiochytrium PKU#Mn16 strain to mainly reveal the differential gene expressions and metabolite profiles.ResultsWhile the supply of 10% DO significantly reduced the rates of biomass and DHA production in the early stages of fermentation, it achieved the highest amounts of biomass (56.7 g/L) and DHA (6.0 g/L) on prolonged fermentation. The transcriptome analyses of the early stage (24 h) of fermentation revealed several genes involved in the central carbon, amino acid, and fatty acid metabolism, which were significantly downregulated at a 10% DO level. The comparative metabolomics results revealed the accumulation of several long-chain fatty acids, amino acids, and other metabolites, supporting the transcriptional regulation under the influence of a low oxygen supply condition. In addition, certain genes involved in antioxidative systems were downregulated under 10% DO level, suggesting a lesser generation of reactive oxygen species that lead to oxidative damage and fatty acid oxidation.ConclusionsThe findings of this study suggest that despite the slow growth and metabolism in the early stage of fermentation of Aurantiochytrium sp. PKU#Mn16, a constant supply of low dissolved oxygen can yield biomass and DHA content better than that with high oxygen supply conditions. The critical information gained in this study will help to further improve DHA production through bioprocess engineering strategies.

Hepatic GATA4 regulates cholesterol and triglyceride homeostasis in collaboration with LXRs.

GATA4 is a transcription factor known for its crucial role in the development of many tissues, including the liver; however, its role in adult liver metabolism is unknown. Here, using high-throughput sequencing technologies, we identified GATA4 as a transcriptional regulator of metabolism in the liver. GATA4 expression is elevated in response to refeeding, and its occupancy is increased at enhancers of genes linked to fatty acid and lipoprotein metabolism. Knocking out GATA4 in the adult liver (Gata4LKO) decreased transcriptional activity at GATA4 binding sites, especially during feeding. Gata4LKO mice have reduced plasma HDL cholesterol and increased liver triglyceride levels. The expression of a panel of GATA4 binding genes involved in hepatic cholesterol export and triglyceride hydrolysis was down-regulated in Gata4LKO mice. We further demonstrate that GATA4 collaborates with LXR nuclear receptors in the liver. GATA4 and LXRs share a number of binding sites, and GATA4 was required for the full transcriptional response to LXR activation. Collectively, these results show that hepatic GATA4 contributes to the transcriptional control of hepatic and systemic lipid homeostasis.

JAZF1: A Metabolic Regulator of Sensitivity to a Polyamine-Targeted Therapy.

We have shown JAZF1 can alter sensitivity of cells and its expression can segregate patient populations into those that do, or do not highly express polyamine genes, leading to better prediction of response to a polyamine targeting therapy.

Protein signalling in response to ex vivo dynamic contractions is independent of training status in rat skeletal muscle.

New Findings What is the central question of this study? Are myofibre protein signalling responses to ex vivo dynamic contractions altered by accustomization to voluntary endurance training in rats? What is the main finding and its importance? In response to ex vivo dynamic muscle contractions, canonical myofibre protein signalling pertaining to metabolic transcriptional regulation, as well as translation initiation and elongation, was not influenced by prior accustomization to voluntary endurance training in rats. Accordingly, intrinsic myofibre protein signalling responses to standardized contractile activity may be independent of prior exercise training in rat skeletal muscle. Skeletal muscle training status may influence myofibre regulatory protein signalling in response to contractile activity. The current study employed a purpose‐designed ex vivo dynamic contractile protocol to evaluate the effect of exercise‐accustomization on canonical myofibre protein signalling for metabolic gene expression and for translation initiation and elongation. To this end, rats completed 8 weeks of in vivo voluntary running training versus no running control intervention, whereupon an ex vivo endurance‐type dynamic contraction stimulus was conducted in isolated soleus muscle preparations from both intervention groups. Protein signalling response by phosphorylation was evaluated by immunoblotting at 0 and 3 h following ex vivo stimulation. Phosphorylation of AMP‐activated protein kinase α‐isoforms and its downstream target, acetyl‐CoA carboxylase, as well as phosphorylation of eukaryotic elongation factor 2 (eEF2) was increased immediately following the dynamic contraction protocol (at 0 h). Signalling for translation initiation and elongation was evident at 3 h after dynamic contractile activity, as evidenced by increased phosphorylation of p70 S6 kinase and eukaryotic translation initiation factor 4E‐binding protein 1, as well as a decrease in phosphorylation of eEF2 back to resting control levels. However, prior exercise training did not alter phosphorylation responses of the investigated signalling proteins. Accordingly, protein signalling responses to standardized endurance‐type contractions may be independent of training status in rat muscle during ex vivo conditions. The present findings add to our current understanding of molecular regulatory events responsible for skeletal muscle plasticity.

Transcriptional regulation of primary and specialized metabolism

Michelle Tang1, Allison Gaudinier1, Baohua Li1, Lifang Zhang2, Christophe Liseron‐Monfils2, Joel Rodriguez‐Medina1, Anne‐Maarit Bagman1, Andrew Olsen2, Doreen Ware2,3, Mary Frank4, Bo Shen4, Daniel J. Kliebenstein1, Siobhan M. Brady11UC Davis, Davis, CA2Cold Spring Harbor Laboratory, Cold Spring Harbor, NY3USDA‐ARS, Albany, NY4DuPont Pioneer, Johnston, IARegulation of plant development requires intricate communication with both primary and specialized metabolism in order to fuel growth. While transcriptional regulation of metabolism is evident from myriad whole genome‐expression analyses, our understanding of which transcriptional regulators are responsible for these changes as well as their underlying mode of action is unclear. I will highlight our efforts on systematic mapping of transcriptional regulators of primary metabolism (nitrogen and central carbon) as well as specialized metabolism (glucosinolates). Network analyses incorporating protein‐DNA interaction data, gene expression and connectivity were used to identify critical regulators, most of which were shown to regulate metabolism via developmental‐ and stress‐conditional processes that coordinate across primary and specialized metabolism. These analyses demonstrate distinct design principles responsible for metabolism between microbes and this multicellular eukaryote.

From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates

Lipids and carbohydrates regulate gene expression by means of molecules that sense these macronutrients and act as transcription factors. The peroxisome proliferator-activated receptor (PPAR), activated by some fatty acids or their derivatives, and the carbohydrate response element binding protein (ChREBP), activated by glucose-derived metabolites, play a key role in metabolic homeostasis, especially in glucose and lipid metabolism. Furthermore, the action of both factors in obesity, diabetes and fatty liver, as well as the pharmacological development in the treatment of these pathologies are indeed of high relevance. In this review we present an overview of the discovery, mechanism of activation and metabolic functions of these nutrient-dependent transcription factors in different tissues contexts, from the nutritional genomics perspective. The possibility of targeting these factors in pharmacological approaches is also discussed. Lipid and carbohydrate-dependent transcription factors are key players in the complex metabolic homeostasis, but these factors also drive an adaptive response to non-physiological situations, such as overeating. Possibly the decisive role of ChREBP and PPAR in metabolic regulation points to them as ideal therapeutic targets, but their pleiotropic functions in different tissues makes it difficult to “hit the mark”.

Histone acylation marks respond to metabolic perturbations and enable cellular adaptation

Acetylation is the most studied histone acyl modification and has been recognized as a fundamental player in metabolic gene regulation, whereas other short-chain acyl modifications have only been recently identified, and little is known about their dynamics or molecular functions at the intersection of metabolism and epigenetic gene regulation. In this study, we aimed to understand the link between nonacetyl histone acyl modification, metabolic transcriptional regulation, and cellular adaptation. Using antibodies specific for butyrylated, propionylated, and crotonylated H3K23, we analyzed dynamic changes of H3K23 acylation upon various metabolic challenges. Here, we show that H3K23 modifications were highly responsive and reversibly regulated by nutrient availability. These modifications were commonly downregulated by the depletion of glucose and recovered based on glucose or fatty acid availability. Depletion of metabolic enzymes, namely, ATP citrate lyase, carnitine acetyltransferase, and acetyl-CoA synthetase, which are involved in Ac-CoA synthesis, resulted in global loss of H3K23 butyrylation, crotonylation, propionylation, and acetylation, with a profound impact on gene expression and cellular metabolic states. Our data indicate that Ac-CoA/CoA and central metabolic inputs are important for the maintenance of histone acylation. Additionally, genome-wide analysis revealed that acyl modifications are associated with gene activation. Our study shows that histone acylation acts as an immediate and reversible metabolic sensor enabling cellular adaptation to metabolic stress by reprogramming gene expression.

Enhanced Adipose Expression of Interferon Regulatory Factor (IRF)-5 Associates with the Signatures of Metabolic Inflammation in Diabetic Obese Patients.

Interferon regulatory factors (IRFs) are emerging as the metabolic transcriptional regulators in obesity/type-2 diabetes (T2D). IRF5 is implicated with macrophage polarization toward the inflammatory M1-phenotype, nonetheless, changes in the adipose expression of IRF5 in T2D and relationship of these changes with other markers of adipose inflammation remain unclear. Therefore, we determined the IRF5 gene expression in subcutaneous adipose tissue samples from 46 T2D patients including 35 obese (Body Mass Index/BMI 33.83 ± 0.42 kg/m2) and 11 lean/overweight individuals (BMI 27.55 ± 0.46 kg/m2) using real-time qRT-PCR. IRF5 protein expression was assessed using immunohistochemistry and confocal microscopy. Fasting plasma glucose, insulin, HbA1c, C-reactive protein, cholesterol, low- and high-density lipoproteins (LDL/HDL), and triglycerides were measured using commercial kits. IRF5 gene expression was compared with that of signature inflammatory markers and several clinico-metabolic indicators. The data (mean ± SEM) show the enhanced adipose IRF5 gene (p = 0.03) and protein (p = 0.05) expression in obese compared to lean/overweight diabetic patients. Adipose IRF5 transcripts in diabetic obese individuals associated positively with those of TNF-α, IL-18, IL-23A, CXCL8, CCL2, CCL7, CCR1/5, CD11c, CD68, CD86, TLR4/7/10, Dectin-1, FGL-2, MyD88, NF-κB, IRF3, and AML1 (p < 0.05). In diabetic lean/overweight subjects, IRF5 expression associated with BMI, body fat %age, glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR, C-reactive protein (CRP), IL-5, and IL-1RL1 expression; while in all T2D patients, IRF5 expression correlated with that of IRF4, TLR2/8, and CD163. In conclusion, upregulated adipose tissue IRF5 expression in diabetic obese patients concurs with the inflammatory signatures and it may represent a potential marker for metabolic inflammation in obesity/T2D.

MaREA4Galaxy: Metabolic reaction enrichment analysis and visualization of RNA-seq data within Galaxy

We present MaREA4Galaxy, a user-friendly tool that allows a user to characterize and to graphically compare groups of samples with different transcriptional regulation of metabolism, as estimated from cross-sectional RNA-seq data. The tool is available as plug-in for the widely-used Galaxy platform for comparative genomics and bioinformatics analyses. MaREA4Galaxy combines three modules. The Expression2RAS module, which, for each reaction of a specified set, computes a Reaction Activity Score (RAS) as a function of the expression level of genes encoding for the associated enzyme. The MaREA (Metabolic Reaction Enrichment Analysis) module that allows to highlight significant differences in reaction activities between specified groups of samples. The Clustering module which employs the RAS computed before as a metric for unsupervised clustering of samples into distinct metabolic subgroups; the Clustering tool provides different clustering techniques and implements standard methods to evaluate the goodness of the results.

Regulation of protein kinase C\u03b4 Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1

Inactivation of the protein complex ‘mechanistic target of rapamycin complex 1’ (mTORC1) can increase the nuclear content of transcriptional regulators of metabolism and apoptosis. Previous studies established that nuclear import of signal transducer and activator of transcription-1 (STAT1) requires the mTORC1-associated adaptor karyopherin-α1 (KPNA1) when mTORC1 activity is reduced. However, the role of other mTORC1-interacting proteins in the complex, including ‘protein kinase C delta’ (PKCδ), have not been well characterized. In this study, we demonstrate that PKCδ, a STAT1 kinase, contains a functional ‘target of rapamycin signaling’ (TOS) motif that directs its interaction with mTORC1. Depletion of KPNA1 by RNAi prevented the nuclear import of PKCδ in cells exposed to the mTORC1 inhibitor rapamycin or amino acid restriction. Mutation of the TOS motif in PKCδ led to its loss of regulation by mTORC1 or karyopherin-α1, resulting in increased constitutive nuclear content. In cells expressing wild-type PKCδ, STAT1 activity and apoptosis were increased by rapamycin or interferon-β. Those expressing the PKCδ TOS mutant exhibited increased STAT1 activity and apoptosis; further enhancement by rapamycin or interferon-β, however, was lost. Therefore, the TOS motif in PKCδ is a novel structural mechanism by which mTORC1 prevents PKCδ and STAT1 nuclear import, and apoptosis.

Identification of Transcriptional Signatures of Colon Tumor Stroma by a Meta-Analysis.

Background The tumor stroma plays pivotal roles in influencing tumor growth, invasion, and metastasis. Transcriptional signatures of colon tumor stroma (CTS) are significantly associated with prognosis of colon cancer. Thus, identification of the CTS transcriptional features could be useful for colon cancer diagnosis and therapy. Methods By a meta-analysis of three CTS gene expression profiles datasets, we identified differentially expressed genes (DEGs) between CTS and colon normal stroma. Furthermore, we identified the pathways, upstream regulators, and protein-protein interaction (PPI) network that were significantly associated with the DEGs. Moreover, we analyzed the enrichment levels of immune signatures in CTS. Finally, we identified CTS-associated gene signatures whose expression was significantly associated with prognosis in colon cancer. Results We identified numerous significantly upregulated genes (such as CTHRC1, NFE2L3, SULF1, SOX9, ENC1, and CCND1) and significantly downregulated genes (such as MYOT, ASPA, KIAA2022, ARHGEF37, BCL-2, and PPARGC1A) in CTS versus colon normal stroma. Furthermore, we identified significantly upregulated pathways in CTS that were mainly involved in cellular development, immune regulation, and metabolism, as well as significantly downregulated pathways in CTS that were mostly metabolism-related. Moreover, we identified upstream TFs (such as SUZ12, NFE2L2, RUNX1, STAT3, and SOX2), kinases (such as MAPK14, CSNK2A1, CDK1, CDK2, and CDK4), and master metabolic transcriptional regulators (MMTRs) (such as HNF1A, NFKB1, ZBTB7A, GATA2, and GATA5) regulating the DEGs. We found that CD8+ T cells were more enriched in CTS than in colon normal stroma. Interestingly, we found that many of the DEGs and their regulators were prognostic markers for colon cancer, including CEBPB, PPARGC1, STAT3, MTOR, BCL2, JAK2, and CDK1. Conclusions The identification of CTS-specific transcriptional signatures may provide insights into the tumor microenvironment that mediates the development of colon cancer and has potential clinical implications for colon cancer diagnosis and treatment.

Pan-cancer analysis of transcriptional metabolic dysregulation using The Cancer Genome Atlas

Understanding metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics in the clinic. Here, using transcriptomic data for 10,704 tumor and normal samples from The Cancer Genome Atlas, across 26 disease sites, we present a novel bioinformatics pipeline that distinguishes tumor from normal tissues, based on differential gene expression for 114 metabolic pathways. We confirm pathway dysregulation in separate patient populations, demonstrating the robustness of our approach. Bootstrapping simulations were then applied to assess the biological significance of these alterations. We provide distinct examples of the types of analysis that can be accomplished with this tool to understand cancer specific metabolic dysregulation, highlighting novel pathways of interest, and patterns of metabolic flux, in both common and rare disease sites. Further, we show that Master Metabolic Transcriptional Regulators explain why metabolic differences exist, can segregate patient populations, and predict responders to different metabolism-targeted therapeutics.

Transcriptional regulation of metabolism in disease: From transcription factors to epigenetics.

Every cell in an individual has largely the same genomic sequence and yet cells in different tissues can present widely different phenotypes. This variation arises because each cell expresses a specific subset of genomic instructions. Control over which instructions, or genes, are expressed is largely controlled by transcriptional regulatory pathways. Each cell must assimilate a huge amount of environmental input, and thus it is of no surprise that transcription is regulated by many intertwining mechanisms. This large regulatory landscape means there are ample possibilities for problems to arise, which in a medical context means the development of disease states. Metabolism within the cell, and more broadly, affects and is affected by transcriptional regulation. Metabolism can therefore contribute to improper transcriptional programming, or pathogenic metabolism can be the result of transcriptional dysregulation. Here, we discuss the established and emerging mechanisms for controling transcription and how they affect metabolism in the context of pathogenesis. Cis- and trans-regulatory elements, microRNA and epigenetic mechanisms such as DNA and histone methylation, all have input into what genes are transcribed. Each has also been implicated in diseases such as metabolic syndrome, various forms of diabetes, and cancer. In this review, we discuss the current understanding of these areas and highlight some natural models that may inspire future therapeutics.

Transcriptional Regulation of Metabolism by SIRT1 and SIRT7.

Sirtuins are a family of evolutionally conserved nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases/deacylases that regulate metabolism. The mammalian sirtuin family consists of seven sirtuins (SIRT1-7). Recent findings have identified critical roles for SIRT1 and SIRT7 in glucose/lipid metabolism in multiple tissues. This review focuses on the metabolic roles of these two sirtuins and the benefits of modulating the activity of sirtuins for the treatment of metabolic diseases such as type 2 diabetes.

Peroxisome proliferator-activated receptor gamma expression in peripheral blood mononuclear cells and angiopoietin-like protein 4 levels in obese children and adolescents

The peroxisome proliferator-activated receptor γ (PPARγ) is highly expressed in adipose tissue and functions as transcriptional regulator of metabolism and adipocyte differentiation. Angiopoietin-like protein 4 (ANGPTL4), a central player in various aspects of energy homoeostasis, is induced by PPARγ. The aim of this study was to evaluate ANGPTL4 plasma levels and PPARγ gene expression in peripheral blood mononuclear cells (PBMCs) of children and adolescents with obesity and their association with metabolic parameters. Seventy children and adolescents (35 obese and 35 age- and gender-matched control subjects), were selected. PBMCs were separated and their total RNA was extracted. After cDNA synthesis, PPARG gene expression was analyzed by real-time PCR. Relative differences in gene expression were calculated by ΔCt method using β-actin as a normalizer. Serum ANGPTL4 and insulin were measured using ELISA, and insulin resistance (IR) was calculated by the homeostatic model assessment of insulin resistance (HOMA-IR). Fasting plasma glucose (FPG), triglyceride, total cholesterol, LDL-C and HDL-C were also measured. The expression of the PPARG gene as well as the plasma ANGPTL4 levels were significantly diminished in obese subjects as compared to control ones. However, they were not significantly different in obese children with IR compared to obese children without IR or in those with or without metabolic syndrome. A significant positive correlation was found between PPARγ and ANGPTL4 (r=0.364, p=0.002). PPARγ expression levels were also significantly correlated with FPG (r=-0.35, p=0.003). PPARγ is decreased in childhood obesity and may be responsible for diminished ANGPTL4 levels.

Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids.

Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism.

Metaboloepigenetics: the Emerging Network in Stem Cell Homeostasis Regulation.

Epigenetics harbours all regulatory information that, beyond nucleotide sequences, allows cells to "make decisions" throughout their lifetime in response to the external environment. The information can be transitory or relatively stable, and is even transmittable either to daughter cells or to the next generations through the germ line. Recent discoveries shed light on numerous connections between metabolites and epigenetic chromatin-modifying enzymes, providing a link between the metabolic state of the cell and epigenetics, and ultimately between metabolism, gene expression and cell fate. In this review, we discuss the possible connections between metabolism and epigenetic regulation of stem cell differentiation and self-renewal. Moreover, we describe pertinent literature that could explain how altered metabolic state and nutrition can contribute to disease development through epigenetic modifications. A special section is dedicated to the emerging link between the circadian clock, metabolic transcriptional regulation by epigenetic mechanisms and their implication in stem cell homeostasis.