Stimulation of Histone Deacetylase Activity by Metabolites of Intermediary Metabolism

Vogelauer, Maria; Krall, Abigail S.; McBrian, Matthew A.; Li, Jingyu; Kurdistani, Siavash K.

doi:10.1074/jbc.m112.362467

Cited by 78 publications

(86 citation statements)

References 37 publications

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“…[45][46][47][48] In addition, endogenous molecules such as sphingosine-1-phosphate and intermediates of nitrogen and carbon Hdac1, Hdac2 and Sin3a in hematopoiesis haematologica | 2014; 99 (8)metabolism were shown to regulate HDAC activity. 49,50 Intriguingly, β-hydroxybutyrate, a major source of energy for mammals during prolonged exercise or starvation and a compound structurally related to HDAC inhibitors, was shown to inhibit class I HDAC and conferred protection against oxidative stress. 51 These observations portray an intricate relationship between cellular metabolism, Hdac1/Hdac2 activity and epigenetic changes.…”

Section: Discussionmentioning

confidence: 99%

Sin3a-associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis

et al. 2014

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Class I histone deacetylases are critical regulators of gene transcription by erasing lysine acetylation. Targeting histone deacetylases using relative non-specific small molecule inhibitors is of major interest in the treatment of cancer, neurological disorders and acquired immune deficiency syndrome. Harnessing the therapeutic potential of histone deacetylase inhibitors requires full knowledge of individual histone deacetylases in vivo. As hematologic malignancies show increased sensitivity towards histone deacetylase inhibitors we targeted deletion of class I Hdac1 and Hdac2 to hematopoietic cell lineages. Here, we show that Hdac1 and Hdac2 together control hematopoietic stem cell homeostasis, in a cell-autonomous fashion. Simultaneous loss of Hdac1 and Hdac2 resulted in loss of hematopoietic stem cells and consequently bone marrow failure. Bone-marrow-specific deletion of Sin3a, a major Hdac1/2 co-repressor, phenocopied loss of Hdac1 and Hdac2 indicating that Sin3a-associated HDAC1/2-activity is essential for hematopoietic stem cell homeostasis. Although Hdac1 and Hdac2 show compensatory and overlapping functions in hematopoiesis, mice expressing mono-allelic Hdac1 or Hdac2 revealed that Hdac1 and Hdac2 contribute differently to the development of specific hematopoietic lineages.

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Section: Discussionmentioning

confidence: 99%

Sin3a-associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis

et al. 2014

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“…Histone acetylation by HDACs creates free acetate incorporated into CoA by acetyl-CoA synthase II(Sakakibara et al, 2009).Kinetic studies of recombinant HDACs show that its activity is induced by such substrates as acetyl-CoA, malonyl-CoA, and HMG CoA, and inhibited by free CoA (Vogelauer et al, 2012), suggesting that metabolic intermediates directly influence HDAC activity. Moreover,HDAC and HAT activities are regulated by the translocation to the nucleus to access their nuclear substrates.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The role dietary of bioactive compounds on the regulation of histone acetylases and deacetylases: A review

Vahid

Zand

Nosrat–Mirshekarlou

et al. 2015

Gene

175

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“…Thus, we found it relevant to compare effects of NADH levels on these novel sirtuin deacylase activities with the effects on deacetylation. Because the Zn 2ϩ -dependent HDACs do not use NAD ϩ as a co-substrate, they were not included in this investigation; indeed, the activity of HDAC1 and -2 has been reported to be insensitive to NADH (74).…”

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confidence: 99%

Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH

Madsen

Andersen

Daoud

et al. 2016

Journal of Biological Chemistry

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Protein lysine posttranslational modification by an increasing number of different acyl groups is becoming appreciated as a regulatory mechanism in cellular biology. Sirtuins are class III histone deacylases that use NAD ؉ as a co-substrate during amide bond hydrolysis. Several studies have described the sirtuins as sensors of the NAD ؉ /NADH ratio, but it has not been formally tested for all the mammalian sirtuins in vitro. To address this problem, we first synthesized a wide variety of peptide-based probes, which were used to identify the range of hydrolytic activities of human sirtuins. These probes included aliphatic ⑀-N-acyllysine modifications with hydrocarbon lengths ranging from formyl (C 1 ) to palmitoyl (C 16 ) as well as negatively charged dicarboxyl-derived modifications. In addition to the well established activities of the sirtuins, "long chain" acyllysine modifications were also shown to be prone to hydrolytic cleavage by SIRT1-3 and SIRT6, supporting recent findings. We then tested the ability of NADH, ADP-ribose, and nicotinamide to inhibit these NAD ؉ -dependent deacylase activities of the sirtuins. In the commonly used 7-amino-4-methylcoumarin-coupled fluorescence-based assay, the fluorophore has significant spectral overlap with NADH and therefore cannot be used to measure inhibition by NADH. Therefore, we turned to an HPLC-MS-based assay to directly monitor the conversion of acylated peptides to their deacylated forms. All tested sirtuin deacylase activities showed sensitivity to NADH in this assay. However, the inhibitory concentrations of NADH in these assays are far greater than the predicted concentrations of NADH in cells; therefore, our data indicate that NADH is unlikely to inhibit sirtuins in vivo. These data suggest a re-evaluation of the sirtuins as direct sensors of the NAD ؉ /NADH ratio.

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Stimulation of Histone Deacetylase Activity by Metabolites of Intermediary Metabolism

Cited by 78 publications

References 37 publications

Sin3a-associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis

Sin3a-associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis

The role dietary of bioactive compounds on the regulation of histone acetylases and deacetylases: A review

Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH

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