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Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression

Chemical inhibitors of histone deacetylase (HDAC) activity are used as experimental tools to induce histone hyperacetylation and deregulate gene transcription, but it is not known whether the inhibition of HDACs plays any part in the normal physiological regulation of transcription. Using both in vi...

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Autores principales: Latham, Tom, Mackay, Logan, Sproul, Duncan, Karim, Muhammed, Culley, Jayne, Harrison, David J, Hayward, Larry, Langridge-Smith, Pat, Gilbert, Nick, Ramsahoye, Bernard H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367171/
https://www.ncbi.nlm.nih.gov/pubmed/22323521
http://dx.doi.org/10.1093/nar/gks066
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author Latham, Tom
Mackay, Logan
Sproul, Duncan
Karim, Muhammed
Culley, Jayne
Harrison, David J
Hayward, Larry
Langridge-Smith, Pat
Gilbert, Nick
Ramsahoye, Bernard H
author_facet Latham, Tom
Mackay, Logan
Sproul, Duncan
Karim, Muhammed
Culley, Jayne
Harrison, David J
Hayward, Larry
Langridge-Smith, Pat
Gilbert, Nick
Ramsahoye, Bernard H
author_sort Latham, Tom
collection PubMed
description Chemical inhibitors of histone deacetylase (HDAC) activity are used as experimental tools to induce histone hyperacetylation and deregulate gene transcription, but it is not known whether the inhibition of HDACs plays any part in the normal physiological regulation of transcription. Using both in vitro and in vivo assays, we show that lactate, which accumulates when glycolysis exceeds the cell’s aerobic metabolic capacity, is an endogenous HDAC inhibitor, deregulating transcription in an HDAC-dependent manner. Lactate is a relatively weak inhibitor (IC(50) 40 mM) compared to the established inhibitors trichostatin A and butyrate, but the genes deregulated overlap significantly with those affected by low concentrations of the more potent inhibitors. HDAC inhibition causes significant up and downregulation of genes, but genes that are associated with HDAC proteins are more likely to be upregulated and less likely to be downregulated than would be expected. Our results suggest that the primary effect of HDAC inhibition by endogenous short-chain fatty acids like lactate is to promote gene expression at genes associated with HDAC proteins. Therefore, we propose that lactate may be an important transcriptional regulator, linking the metabolic state of the cell to gene transcription.
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spelling pubmed-33671712012-06-05 Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression Latham, Tom Mackay, Logan Sproul, Duncan Karim, Muhammed Culley, Jayne Harrison, David J Hayward, Larry Langridge-Smith, Pat Gilbert, Nick Ramsahoye, Bernard H Nucleic Acids Res Gene Regulation, Chromatin and Epigenetics Chemical inhibitors of histone deacetylase (HDAC) activity are used as experimental tools to induce histone hyperacetylation and deregulate gene transcription, but it is not known whether the inhibition of HDACs plays any part in the normal physiological regulation of transcription. Using both in vitro and in vivo assays, we show that lactate, which accumulates when glycolysis exceeds the cell’s aerobic metabolic capacity, is an endogenous HDAC inhibitor, deregulating transcription in an HDAC-dependent manner. Lactate is a relatively weak inhibitor (IC(50) 40 mM) compared to the established inhibitors trichostatin A and butyrate, but the genes deregulated overlap significantly with those affected by low concentrations of the more potent inhibitors. HDAC inhibition causes significant up and downregulation of genes, but genes that are associated with HDAC proteins are more likely to be upregulated and less likely to be downregulated than would be expected. Our results suggest that the primary effect of HDAC inhibition by endogenous short-chain fatty acids like lactate is to promote gene expression at genes associated with HDAC proteins. Therefore, we propose that lactate may be an important transcriptional regulator, linking the metabolic state of the cell to gene transcription. Oxford University Press 2012-06 2012-02-09 /pmc/articles/PMC3367171/ /pubmed/22323521 http://dx.doi.org/10.1093/nar/gks066 Text en © The Author(s) 2012. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Gene Regulation, Chromatin and Epigenetics
Latham, Tom
Mackay, Logan
Sproul, Duncan
Karim, Muhammed
Culley, Jayne
Harrison, David J
Hayward, Larry
Langridge-Smith, Pat
Gilbert, Nick
Ramsahoye, Bernard H
Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression
title Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression
title_full Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression
title_fullStr Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression
title_full_unstemmed Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression
title_short Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression
title_sort lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression
topic Gene Regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367171/
https://www.ncbi.nlm.nih.gov/pubmed/22323521
http://dx.doi.org/10.1093/nar/gks066
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