Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription

Boukouris, Aristeidis E.; Zervopoulos, Sotirios; Michelakis, Evangelos D.

doi:10.1016/j.tibs.2016.05.013

Cited by 243 publications

(218 citation statements)

References 135 publications

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“…It is reasonable to suppose that propionylglycine, crotonylglycine and butyrylglycine (Table 2) are also substrates of ACY1. Broader metabolomic studies on larger groups of GA3 and ACY1-deficient individuals could be worthwhile, particularly in an era where many metabolic enzymes are newly recognised to have additional diverse and significant "moonlighting" roles in other cellular processes (Zschocke 2012;Vilardo and Rossmanith 2015;Boukouris et al 2016). …”

Section: Discussionmentioning

confidence: 99%

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment

et al. 2017

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Glutaric aciduria type 3 (GA3) is associated with decreased conversion of free glutaric acid to glutaryl-coA, reflecting deficiency of succinate-hydroxymethylglutarate coA-transferase, caused by variants in the SUGCT (C7orf10) gene. GA3 remains less well known, characterised and understood than glutaric aciduria types 1 and 2. It is generally considered a likely "non-disease," but this is based on limited supporting information, with only nine individuals with GA3 described in the literature. Clinicians encountering a patient with GA3 therefore still face a dilemma of whether or not this should be dismissed as irrelevant.We have identified three unrelated Canadian patients with GA3. Two came to clinical attention because of symptoms, while the third was identified by a population urine-based newborn screening programme and has so far remained asymptomatic. We describe the clinical histories, biochemical characterisation and genotypes of these individuals. Examination of allele frequencies underlines the fact that GA3 is underdiagnosed. While one probable factor is that some GA3 patients remain asymptomatic, we highlight other plausible reasons whereby this diagnosis might be overlooked.Gastrointestinal disturbances were previously reported in some GA3 patients. In one of our patients, severe episodes of cyclic vomiting were the major problem. A trial of antibiotic treatment, to minimise bacterial GA production, was followed by significant clinical improvement.At present, there is insufficient evidence to define any specific clinical phenotype as attributable to GA3. However, we consider that it would be premature to assume that this condition is completely benign in all individuals at all times.

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Section: Discussionmentioning

confidence: 99%

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment

et al. 2017

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“…Pyruvate, the end product of the glycolysis, fuels the PDC. However, there is no evidence for nuclear glycolysis, although many glycolytic enzymes have been observed in the nucleus (Boukouris et al 2016). For some of those, like glyceraldehyde-3-phosphate dehydrogenase (GAPDH), it seems clear that they are not enzymatically active in the nucleus but perform moonlighting functions (see below).…”

Section: Nuclear Synthesis Of Acetyl-coamentioning

confidence: 99%

Undercover: gene control by metabolites and metabolic enzymes

2016

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To make the appropriate developmental decisions or maintain homeostasis, cells and organisms must coordinate the expression of their genome and metabolic state. However, the molecular mechanisms that relay environmental cues such as nutrient availability to the appropriate gene expression response remain poorly understood. There is a growing awareness that central components of intermediary metabolism are cofactors or cosubstrates of chromatin-modifying enzymes. As such, their concentrations constitute a potential regulatory interface between the metabolic and chromatin states. In addition, there is increasing evidence for a direct involvement of classic metabolic enzymes in gene expression control. These dual-function proteins may provide a direct link between metabolic programing and the control of gene expression. Here, we discuss our current understanding of the molecular mechanisms connecting metabolism to gene expression and their implications for development and disease.Metabolism and gene regulation are two fundamental biological processes that are essential to all living organisms. Homeostasis, cell growth, and differentiation all require the coordination of metabolic state and gene expression programs. Nevertheless, how expression of the genome adapts to metabolic state or environmental changes is not well understood. One level of regulation involves signal transduction pathways that control key transcription factors that act as master regulators of gene expression programs. In addition, post-translational modifications (PTMs) of chromatin play a major role in the activation or repression of gene transcription. These include acetylation, methylation, and phosphorylation of the histones and DNA methylation. Some of these chromatin modifications are involved in the maintenance of stable patterns of gene expression, usually referred to as epigenetic regulation. Pertinently, the activity of enzymes that modulate chromatin is critically dependent on central metabolites as cofactors or cosubstrates. Thus, the availability of metabolites that are required for the activity of histone-modifying enzymes may connect metabolism to chromatin structure and gene expression. Finally, selective metabolic enzymes act in the nucleus to adjust gene transcription in response to changes in metabolic state. Here, we review the interface between metabolism and gene transcription. We focus on the molecular mechanisms involved and discuss unresolved issues and implications for development and disease. The basics of metabolism and gene expression controlMetabolism is the total of all chemical reactions in cells and organisms that maintain life. Metabolism can be divided into two classes: catabolic processes (the breakdown of molecules that usually results in the release of energy) and anabolic processes (the synthesis of components such as proteins, lipids, and nucleic acids, which costs energy). Cellular (or intermediary) metabolism is organized in separate chemical pathways formed by a chain of linked enzymatic reactions in wh...

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“…18 Because the "moonlighting" of ACPEs in the nucleus apparently solves the problem that acetyl-CoA is not permeable through mitochondrial membranes and, owing to its instability, needs to be produced close to where it is needed, it remains to be determined whether the metformin-induced restraining of mitochondrial-dependent biosynthesis of metabolic intermediates imposes either global changes in nuclear acetyl-CoA levels (and therefore regulates global histone acetylation) or small, localized changes in nuclear acetyl-CoA levels (and therefore regulates selective histone acetylation). 18 Although the latter scenario appears counterintuitive, it should be noted that pyruvate kinase (PK), especially the isoenzyme PKM2, and mitochondrial PDC are translocated and form a complex in the nucleus with a histone acetyl transferase to locally produce acetyl-CoA and drive specific acetylation of histone marks. 57,58 Moreover, nuclear PKM2 operates not only as a biosynthetic enzyme to produce pyruvate to be used by PDC for nuclear generation of acetyl-CoA, but also as a non-canonical kinase that binds and phosphorylates histone H3 at T11 to promote subsequent acetylation of H3 at K9.…”

Section: Highly Anabolic Brca1 Haploinsufficient Cells Exhibit Increamentioning

confidence: 99%

“…3,4,[7][8][9][10][11] Although it remains intriguing how aging-related changes in cellular metabolism might control the layers of epigenetic instructions that influence cell fate without altering the primary DNA sequence, it should be acknowledged that the multiple processes involved in the alteration of the chromatin state, including post-translational modifications of histone proteins, incorporation of specific histone variants, methylation of DNA and ATP-dependent chromatin remodeling, are likely the pivotal molecular bridges that mediate the direct communication between the metabolic and the chromatin state, and the consequent epigenetic targeting of cell fate regulatory genes. [12][13][14][15][16][17][18][19][20] Indeed, because the usage of metabolic intermediates as substrates for chromatin-modifying enzymes provides a direct link between the metabolic state of the cell and epigenetics, one can envision that the spatio-temporal distribution of the levels and types of specific metabolites might operate as key cancer-related molecular events, rendering a cell susceptible to the epigenetic rewiring required for the acquisition of an aberrant cancer cell state and, concurrently, of refractoriness to normal differentiation.…”

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confidence: 99%

Metformin targets histone acetylation in cancer-prone epithelial cells

et al. 2016

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The usage of metabolic intermediates as substrates for chromatin-modifying enzymes provides a direct link between the metabolic state of the cell and epigenetics. Because this metabolism-epigenetics axis can regulate not only normal but also diseased states, it is reasonable to suggest that manipulating the epigenome via metabolic interventions may improve the clinical manifestation of age-related diseases including cancer. Using a model of BRCA1 haploinsufficiency-driven accelerated geroncogenesis, we recently tested the hypothesis that: 1.) metabolic rewiring of the mitochondrial biosynthetic nodes that overproduce epigenetic metabolites such as acetyl-CoA should promote cancer-related acetylation of histone H3 marks; 2.) metformin-induced restriction of mitochondrial biosynthetic capacity should manifest in the epigenetic regulation of histone acetylation. We now provide one of the first examples of how metformin-driven metabolic shifts such as reduction of the 2-carbon epigenetic substrate acetyl-CoA is sufficient to correct specific histone H3 acetylation marks in cancer-prone human epithelial cells. The ability of metformin to regulate mitonuclear communication and modulate the epigenetic landscape in genomically unstable pre-cancerous cells might guide the development of new metabolo-epigenetic strategies for cancer prevention and therapy. KEYWORDS BRCA1; epigenetics; histone acetylation; metformin; mitochondria While metabolic rewiring of cancer cells can be a direct consequence of the concerted action of oncogenes and tumor suppressor genes that drive aberrant growth of cancer tissues, altered metabolism might also play a primary, causative role in oncogenesis. Accordingly, metabolic reprogramming is increasingly appreciated as a candidate hallmark of tumorigenesis. [1][2][3][4][5] In a recently proposed metabolism-centered model of carcinogenesis, known as geroncogenesis 2 the possibility of acquiring genetic aberrations increases when aging itself operates as a driver of cancer-like metabolic landscapes. Tumor formation might therefore depend not only on accumulating mutations in the genome, but also on the decline in the homeostasis or metabolic health that naturally occurs in aging cells. Indeed, after many years of being subordinated to the nucleus as the commander-in-chief, able to initiate biological events, the capacity of metabolism to independently dictate cellular actions is increasingly recognized among most cell biologists. Accordingly, the research community now acknowledges that aging-driven alteration of metabolic homeostasis might be sufficient to favor an imbalance in self-amplifying metabolic landscapes that ultimately manifest as aging-driven diseases, including cancer. 6Metabolic programs: From anabolic supporters of genomic instability to epigenetic regulators of carcinogenesisThe metabolic health of our cells might be a key determinant factor pushing the risk balance or cancer risk-meter toward health or the risk of cancer.1,2 On the one hand, genomic instability, a charac...

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Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription

Cited by 243 publications

References 135 publications

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment

Undercover: gene control by metabolites and metabolic enzymes

Metformin targets histone acetylation in cancer-prone epithelial cells

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