Quantitative sub-cellular acyl-CoA analysis reveals distinct nuclear regulation

Trefely, Sophie; Huber, Katharina; Liu, Joyce F.; Noji, Michael; Stransky, Stephanie; Singh, Jay; Doan, Mary T.; Lovell, Claudia D.; Krusenstiern, Eliana von; Jiang, Helen; Bostwick, Anna; Pepper, Hannah L.; Izzo, Luke; Zhao, Steven; Xu, Jimmy P.; Bedi, Kenneth; Rame, J. Eduardo; Bogner‐Strauß, Juliane Gertrude; Mesaros, Clementina; Wellen, Kathryn E.; Snyder, Nathaniel W.

doi:10.1101/2020.07.30.229468

Cited by 7 publications

(13 citation statements)

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“…Findings that other acyl‐CoAs besides acetyl‐CoA can occur in the nucleus and function as acyl donors for various histone‐modifying enzymes, added additional complexity to the panel of histone modifications (Pietrocola et al , 2015; preprint: Trefely et al , 2020a). In line with this, metabolic enzymes involved in the generation of these additional acyl‐CoAs have been recently detected in the nucleus.…”

Section: Introduction: Histone Lysine Acylations and Metabolismmentioning

confidence: 99%

Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism

2021

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In eukaryotic cells, DNA is tightly packed with the help of histone proteins into chromatin. Chromatin architecture can be modified by various post-translational modifications of histone proteins. For almost 60 years now, studies on histone lysine acetylation have unraveled the contribution of this acylation to an open chromatin state with increased DNA accessibility, permissive for gene expression. Additional complexity emerged from the discovery of other types of histone lysine acylations. The acyl group donors are products of cellular metabolism, and distinct histone acylations can link the metabolic state of a cell with chromatin architecture and contribute to cellular adaptation through changes in gene expression. Currently, various technical challenges limit our full understanding of the actual impact of most histone acylations on chromatin dynamics and of their biological relevance. In this review, we summarize the state of the art and provide an overview of approaches to overcome these challenges. We further discuss the concept of subnuclear metabolic niches that could regulate local CoA availability and thus couple cellular metabolisms with the epigenome.

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Section: Introduction: Histone Lysine Acylations and Metabolismmentioning

confidence: 99%

Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism

2021

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“…Metabolites are quantified via liquid chromatography/mass spectrometry. Wellen showed that SILEC‐SF can successfully detect predicted compartment‐specific changes in acyl‐CoA abundance under hypoxic conditions 14,15 . Wellen's group plans to use SILEC‐SF to understand the pathways through which acyl‐CoAs are transported to or generated in the nucleus and how are these pathways mediate biological responses.…”

Section: Metabolic Control Of Gene Expression and Developmental Decisionsmentioning

confidence: 99%

Metabolic decisions in development and disease—a Keystone Symposia report

Cable¹,

Pourquié

Wellen

et al. 2021

Annals of the New York Academy of Sciences

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There is an increasing appreciation for the role of metabolism in cell signaling and cell decision making. Precise metabolic control is essential in development, as evident by the disorders caused by mutations in metabolic enzymes. The metabolic profile of cells is often cell‐type specific, changing as cells differentiate or during tumorigenesis. Recent evidence has shown that changes in metabolism are not merely a consequence of changes in cell state but that metabolites can serve to promote and/or inhibit these changes. Metabolites can link metabolic pathways with cell signaling pathways via several mechanisms, for example, by serving as substrates for protein post‐translational modifications, by affecting enzyme activity via allosteric mechanisms, or by altering epigenetic markers. Unraveling the complex interactions governing metabolism, gene expression, and protein activity that ultimately govern a cell's fate will require new tools and interactions across disciplines. On March 24 and 25, 2021, experts in cell metabolism, developmental biology, and human disease met virtually for the Keystone eSymposium, “Metabolic Decisions in Development and Disease.” The discussions explored how metabolites impact cellular and developmental decisions in a diverse range of model systems used to investigate normal development, developmental disorders, dietary effects, and cancer‐mediated changes in metabolism.

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“…We confirm the changes in protein propionylation during myogenic differentiation and newly suggest that increasing these propionylation levels by extracellular exposure to propionate has cellular consequences. Levels of propionyl-CoA drive propionylation and increased cellular levels of propionyl-CoA have been observed in conditions of serum starvation, likely by the catabolism of amino acids, such as isoleucine (Trefely et al 2020). Therefore, we hypothesise that metabolic events that increase propionyl-CoA levels, such as increased protein catabolism, could have unique signalling roles, possibly via protein and histone propionylation.…”

Section: + Propionate Control Propionylation 43 Kdamentioning

confidence: 91%

“…This suggests that the concentration of propionyl-CoA must be higher in the nucleus, possibly due to propionyl-CoA compartmentalisation. Indeed, it was shown that the acetyl-CoA:propionyl-CoA ratio was approximately 4 in whole-cell lysates, while in the nucleus the two acyl-CoAs were found in equimolar concentrations (Trefely et al 2020). In this way, small changes in cellular propionyl-CoA levels can be amplified due to the compartmentalisation of propionyl-CoA in the nucleus.…”

Section: + Propionate Control Propionylation 43 Kdamentioning

confidence: 99%

“…Chapter 7 140 propionyl-CoA, the substrate for propionylation, can be derived from the breakdown of cholesterol, odd-chain fatty acids and the amino acids isoleucine, valine, threonine and methionine (Sbaï et al 1994). Due to the role of propionyl-CoA in metabolism and because propionylation is likely driven by levels of propionyl-CoA, situations in which propionyl-CoA levels are altered, protein propionylation could be functionally important, for example during protein breakdown (Trefely et al 2020).…”

Section: Introductionmentioning

confidence: 99%

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Muscle mitochondrial health : ageing, physical activity and molecular mechanisms

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2 and preventing sarcopenia, will likely have a tremendous impact on patients and society, especially in view of the current demographic trends. The ageing muscleSkeletal muscle is the largest organ in the body, accounting for up to 40% of body mass. The primary role of skeletal muscle is to allow one to maintain posture and, by contraction, to move the skeletal system. Skeletal muscle is one of the most plastic tissues in the human body. It is able to regenerate completely in response to injury (Chargé and Rudnicki 2004) or increase in mass, strength and efficiency following repeated physical exercise stimuli (Hughes et al. 2018). Nevertheless, almost half of the skeletal muscle mass is expected to be lost over a lifetime (Janssen et al. 2002). Skeletal muscle mass peaks in a person's mid-20s, after which the decline is thought to be gradual. However, the first changes become notable after the 5 th decade of life (Lexell et al. 1988). Thereafter, the rate of muscle loss starts to accelerate (Janssen et al. 2002), which also becomes apparent from the changes in total energy expenditure (Speakman and Westerterp 2010). Besides the primary role of skeletal muscle in movement, it also has an important role in metabolism, thermoregulation and is the largest store of glucose and amino acids in the body (Shulman et al. 1990).Therefore, losing muscle mass, besides impairing physical functioning, also has metabolic implications, which links it with other age-related diseases, such as type 2 diabetes (Park et al. 2007).The underlying causes of loss of muscle strength and quality with age are hypothesised to be caused by hallmarks of ageing, such as loss of proteostasis, altered cellular communication and stem cell exhaustion (López-Otín et al. 2013a). This manifests itself as, among other things, decreased innervation (Gonzalez-Freire et al. 2014), decreased muscle regeneration (Carosio et al. 2011), decreased protein synthesis (Balagopal et al. 1997), decreased circulating anabolic hormones (Sakuma and Yamaguchi 2012), low-grade inflammation (Dalle et al. 2017), decreased mitochondrial capacity (Carter et al. 2015) or a Chapter 1 Chapter 1 10MR scanners are not portable and therefore on-site measurements are not possible. In the most recent decades, there has emerged a novel method to non-invasively assess muscle mitochondrial capacity in vivo, namely near-infrared spectroscopy (NIRS). This method offers solutions for the practical disadvantages inherent to 31 P-MRS, such as increased portability and relatively lower costs. A novel method to measure mitochondrial capacity non-invasively, using near-infrared spectroscopyNIRS assessment of mitochondrial capacity makes use of light in a specific region in the nearinfrared light spectrum (700-850 nm), of which a significant amount can penetrate biological tissues, where the major absorbing chromophores are haemoglobin and myoglobin. Haemoglobin and myoglobin have oxygen-dependent absorption changes in this spectrum, making it possible to distinguish oxyhaemoglobin/myoglobin (...

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Quantitative sub-cellular acyl-CoA analysis reveals distinct nuclear regulation

Cited by 7 publications

References 91 publications

Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism

Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism

Metabolic decisions in development and disease—a Keystone Symposia report

Muscle mitochondrial health : ageing, physical activity and molecular mechanisms

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