Does chromatin function as a metabolite reservoir?

Nirello, Vinícius D.; Paula, Dieggo Rodrigues de; Araújo, Nathália V.P.; Varga‐Weisz, Patrick

doi:10.1016/j.tibs.2022.03.016

Cited by 9 publications

(14 citation statements)

References 16 publications

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“…Total cellular acetyl-CoA has been measured in the range of 2x10 -5 to 2x10 -4 pmol/cell (Figs 1 and 2) [4,30]. Therefore, at complete maximum acetylation capacity, we estimate that histone tails have the potential to provide 10-100 times the whole-cell acetyl-CoA, agreeing with previous estimates [12,15]. However, measurements (relative and stoichiometric) of acetylation occupancy at specific sites indicate that physiological occupancy averages between 4-13% under standard culture conditions across primary and immortalized cell lines (Fig 1A ; S1 Table) [17,[30][31][32][33][34][35][36].…”

Section: Estimating the Acetate Storage Capacity Of Histonessupporting

confidence: 90%

“…Notably, bulk histone acetylation is sensitive to acetyl-CoA availability, and the supply of acetyl-CoA for acetylation of specific histone acetylation marks is important for gene regulation in contexts such as cell differentiation [3-10]. However, whether histone acetylation plays roles beyond gene regulation remains poorly understood [11][12][13][14][15][16].Homeostatic turnover of histone acetylation occurs over a timeframe of minutes to hours in mammalian cell culture under stable nutrient conditions. This dynamic turnover is facilitated by removal and conversion of acetylation marks to free acetate through the action of lysine deacetylases (KDACs) [17][18][19][20].…”

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confidence: 99%

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confidence: 99%

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Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism

Soaita

Megill

Kantner

et al. 2022

Preprint

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The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces acetyl-coenzyme-A (acetyl-CoA), which fuels various metabolic pathways and is also the acyl donor for protein lysine acetylation. Notably, histone acetylation is sensitive to acetyl-CoA availability and nutrient replete conditions induce a substantial accumulation of acetylation on histones. Deacetylation releases acetate, which can be recycled to acetyl-CoA, suggesting that deacetylation could be mobilized as an acetyl-CoA source to feed downstream metabolic processes under nutrient depletion. While the notion of histones as a metabolic reservoir has been frequently proposed, experimental evidence has been lacking. Therefore, to test this concept directly, we developed an experimental system to trace deacetylation-derived acetate and its incorporation into acetyl-CoA, using13C2-acetate in ATP citrate lyase-deficient fibroblasts (Acly-/- MEFs), which are primarily dependent on acetate for protein acetylation. We find that dynamic protein deacetylation in Acly-/- MEFs contributes carbons to acetyl-CoA and proximal downstream metabolites. However, there is no significant effect on acyl-CoA pool sizes, and even at maximal acetylation, deacetylation transiently supplies approximately 9% of cellular acetyl-CoA. Together, our data reveal that although protein acetylation is dynamic and sensitive to nutrient availability, its potential for maintaining cellular acetyl-CoA-dependent metabolic pathways is limited compared to cellular demand.

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Section: Estimating the Acetate Storage Capacity Of Histonessupporting

confidence: 90%

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confidence: 99%

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confidence: 99%

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Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism

Soaita

Megill

Kantner

et al. 2022

Preprint

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“…Deepening studies about “classical” PTMs, such as acetylation and methylation, coupled with studies about “non-classical” PTMs, such as lysine acylation, would allow a better understanding of these PTMs, their interactions, and their role in filamentous fungi. Recent views of the dynamics of histone PTMs deposition and removal underline a possible role of chromatin to store chemical groups, such as acetate derived from acetyl-CoA, to be released when the cell needs it (discussed in [ 182 ]). For example, histone deacetylation may serve to release acetate upon starvation, to renew the pool of acetyl-CoA for metabolism (reviewed by [ 183 ]).…”

Section: Discussionmentioning

confidence: 99%

Post-Translational Modifications of Histones Are Versatile Regulators of Fungal Development and Secondary Metabolism

Etier

Dumetz

Chéreau

et al. 2022

Toxins

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Chromatin structure is a major regulator of DNA-associated processes, such as transcription, DNA repair, and replication. Histone post-translational modifications, or PTMs, play a key role on chromatin dynamics. PTMs are involved in a wide range of biological processes in eukaryotes, including fungal species. Their deposition/removal and their underlying functions have been extensively investigated in yeasts but much less in other fungi. Nonetheless, the major role of histone PTMs in regulating primary and secondary metabolisms of filamentous fungi, including human and plant pathogens, has been pinpointed. In this review, an overview of major identified PTMs and their respective functions in fungi is provided, with a focus on filamentous fungi when knowledge is available. To date, most of these studies investigated histone acetylations and methylations, but the development of new methodologies and technologies increasingly allows the wider exploration of other PTMs, such as phosphorylation, ubiquitylation, sumoylation, and acylation. Considering the increasing number of known PTMs and the full range of their possible interactions, investigations of the subsequent Histone Code, i.e., the biological consequence of the combinatorial language of all histone PTMs, from a functional point of view, are exponentially complex. Better knowledge about histone PTMs would make it possible to efficiently fight plant or human contamination, avoid the production of toxic secondary metabolites, or optimize the industrial biosynthesis of certain beneficial compounds.

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“…Cell excitation and calcium handling, as metabolically demanding processes, may be considered positively regulated during growth and hypertrophy, and downregulated during ischemia or other conditions when conservation of resources is needed. The prominent role played by sirtuins, especially the NAD+ dependent SIRT3-5 in regulating cardiac ion channels ( Figures 2-4 and Figure 7 ), reflects their role as linkers between metabolic state and post-translational modifications to control transcription according to available resources[47, 48].…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent transcriptional control of cardiac electrophysiology by histone acetylation modifiers based on the GTEx database

Pressler

Horvath

Entcheva

2022

Preprint

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Development of safer drugs based on epigenetic modifiers, e.g. histone deacetylase inhibitors (HDACi), requires better understanding of their effects on cardiac electrophysiology. Using RNAseq data from the genotype-tissue-expression database (GTEx), we created models that link the abundance of chromatin modifiers, such as histone acetylation enzymes (HDAC/SIRT/HATs), and the gene expression of ion channels (IC) via select cardiac transcription factors (TFs) in male and female adult human hearts (left ventricle, LV). Gene expression data (transcripts per million, TPM) from GTEx donors (21 to 70 y.o.) were filtered, normalized and transformed to Euclidian space to allow quantitative comparisons in 84 female and 158 male LVs. Sex-specific partial least-square (PLS) regression models, linking gene expression data for HDAC/SIRT/HATs to TFs and to ICs gene expression, revealed tight co-regulation of cardiac ion channels by HDAC/SIRT/HATs, with stronger clustering in the male LV. Co-regulation of genes encoding excitatory and inhibitory processes in cardiac tissue by the histone modifiers may help their predominantly net-neutral effects on cardiac electrophysiology. ATP1A1, encoding for the Na/K pump, represented an outlier - with orthogonal regulation by the histone modifiers to most of the ICs. The HDAC/SIRT/HAT effects were mediated by strong (+) TF regulators of ICs, e.g. MEF2A and TBX5, in both sexes. Furthermore, for male hearts, PLS models revealed a stronger (+)/(-) mediatory role on ICs for NKX25 and TGF1B/KLF4, respectively, while RUNX1 exhibited larger (-) TF effects on ICs in females. Male-trained PLS models of HDAC/SIRT/HAT effects on ICs underestimated the effects on some ICs in females. Insights from the GTEx dataset about the co-expression and transcriptional co-regulation of histone-modifying enzymes, transcription factors and key cardiac ion channels in a sex-specific manner can help inform safer drug design.

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Does chromatin function as a metabolite reservoir?

Cited by 9 publications

References 16 publications

Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism

Dynamic protein deacetylation is a limited carbon source for acetyl-CoA-dependent metabolism

Post-Translational Modifications of Histones Are Versatile Regulators of Fungal Development and Secondary Metabolism

Sex-dependent transcriptional control of cardiac electrophysiology by histone acetylation modifiers based on the GTEx database

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