Chromatin: a capacitor of acetate for integrated regulation of gene expression and cell physiology

Kurdistani, Siavash K.

doi:10.1016/j.gde.2014.06.002

Cited by 38 publications

(34 citation statements)

References 38 publications

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“…However, bulk levels of chromatin PTMs can vary considerably between different tissues or developmental stages or in cancer cells. In particular, low levels of global histone acetylation or methylation are associated with more aggressive cancers and poor patient outcome (Kurdistani 2011(Kurdistani , 2014Greer and Shi 2012). These global changes are difficult to reconcile with gene-specific transcription programs.…”

Section: Acetyl-coa Dynamics and Chromatin Acetylation In Cancer Cellsmentioning

confidence: 99%

“…Given the high abundance of histones, however, chromatin acetylation may have effects beyond gene control. Acetylated histones might function as a storage site for acetate to be released by HDACs when the need arises (Kurdistani 2014). Acetate may then be used for acetyl-CoA production (Comerford et al 2014).…”

Section: Acetyl-coa Dynamics and Chromatin Acetylation In Cancer Cellsmentioning

confidence: 99%

“…Acetate may then be used for acetyl-CoA production (Comerford et al 2014). Kurdistani and coworkers (McBrian et al 2013;Kurdistani 2014) made a compelling argument for histone acetylation as a regulator of intracellular pH. Lowering of the intracellular pH results in global deacetylation of histones with concomitant secretion of acetate anions and protons into the extracellular environment.…”

Section: Acetyl-coa Dynamics and Chromatin Acetylation In Cancer Cellsmentioning

confidence: 99%

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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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Section: Acetyl-coa Dynamics and Chromatin Acetylation In Cancer Cellsmentioning

confidence: 99%

Section: Acetyl-coa Dynamics and Chromatin Acetylation In Cancer Cellsmentioning

confidence: 99%

Section: Acetyl-coa Dynamics and Chromatin Acetylation In Cancer Cellsmentioning

confidence: 99%

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Undercover: gene control by metabolites and metabolic enzymes

2016

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“…*P < 0.05; **P < 0.01; † P < 0.005; † † P < 0.001. (15,16). The ratio of BHB to AcAc is governed by the cellular NADH/NAD + ratio (Fig.…”

Section: Backgrounds (>10 Generations) Hippocampal Gene Expression Pmentioning

confidence: 99%

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

Benjamin

Pilarowski

Carosso

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

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Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.

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“…One such modification is histone acetylation which relaxes chromatin structure by loosening the interaction with DNA, thereby facilitating processes such as DNA repair and replication, and gene transcription [1]. Acetylated histone regions have been found around actively expressed genes, in the promoter, enhancer and super-enhancer, and in transcribed regions [2,3]. A link between aberrant histone acetylation and cancer has been reported in many studies, leading to intensive efforts toward interfering with the enzymes involved in controlling this PTM [3,4].…”

mentioning

confidence: 99%

Targeting BET Bromodomains for Cancer Treatment

et al. 2015

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The bromodomain and extraterminal (BET) subfamily of bromodomain-containing proteins has emerged in the last few years as an exciting, novel target group. BRD4, the best studied BET protein, is implicated in a number of hematological and solid tumors. This is linked to its role in modulating transcription elongation of essential genes involved in cell cycle and apoptosis such as c-Myc and BCL2. Potent BET inhibitors with promising antitumor efficacy in a number of preclinical cancer models have been identified in recent years. This led to clinical studies focusing mostly on the treatment of leukemia and lymphoma, and first encouraging signs of efficacy have already been reported. Here we discuss the biology of BRD4, its known interaction partners and implication in different tumor types. Further, we summarize the current knowledge on BET bromodomain inhibitors.

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Chromatin: a capacitor of acetate for integrated regulation of gene expression and cell physiology

Cited by 38 publications

References 38 publications

Undercover: gene control by metabolites and metabolic enzymes

Undercover: gene control by metabolites and metabolic enzymes

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

Targeting BET Bromodomains for Cancer Treatment

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