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

Latham T, Mackay L, Sproul D, Karim M, Culley J, Harrison DJ, Hayward L, Langridge-Smith P, Gilbert N, Ramsahoye BH - Nucleic Acids Res. (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, SIRCAMS, UK.

ABSTRACT
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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HDAC inhibition preferentially up-regulates HDAC-associated genes. (A) The probability of significant gene deregulation in CD4 cells after a 2 h exposure to high-dose butyrate and TSA. (B and C) Analysis of probes with expression values between 1000 and 5000 in CD4 cells. HDAC-associated genes/probes are more likely to be significantly upregulated (B) and less likely to be significantly downregulated (C) when compared with the overall probability of being up or downregulated on the array [horizontal lines (Chi-squared test)]. *P < 0.05; **P < 0.01; ***P < 0.001.
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gks066-F5: HDAC inhibition preferentially up-regulates HDAC-associated genes. (A) The probability of significant gene deregulation in CD4 cells after a 2 h exposure to high-dose butyrate and TSA. (B and C) Analysis of probes with expression values between 1000 and 5000 in CD4 cells. HDAC-associated genes/probes are more likely to be significantly upregulated (B) and less likely to be significantly downregulated (C) when compared with the overall probability of being up or downregulated on the array [horizontal lines (Chi-squared test)]. *P < 0.05; **P < 0.01; ***P < 0.001.

Mentions: We used t-tests (P < 0.05) to assess significance of deregulation and found that the probability of detecting significant deregulation by HDAC inhibitors varied with the expression values of probes (Figure 5A). The greatest probability of deregulation occurred in probes with expression values between 1000 and 5000 in control cells. A similar pattern was seen with lactate and butyrate on our Illumina expression arrays (Supplementary Figure S2A and B). Interestingly in the Wang et al, dataset genes were more likely to be significantly downregulated than upregulated by HDAC inhibition (Figure 5A). However, when we looked specifically at the genes that were associated with HDAC proteins, we found highly significant effects on gene expression. Genes (probes) with expression values between 1000 and 5000 in control cells were significantly more likely to be upregulated by HDAC inhibition if they were associated with either of the HDACs (Figure 5B). Conversely the probability of being downregulated was less for probes that were associated with each of the HDACs (Figure 5C). Thus, while genes can be both upregulated and downregulated by exposure to HDAC inhibitors, the association of genes with HDAC proteins increases their likelihood of upregulation. This indicates that, rather than controlling the repression of non-expressed genes, HDACs exert a repressive effect on expressed genes and this effect would be modulated by endogenous HDAC inhibitors such as lactate.Figure 5.


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

Latham T, Mackay L, Sproul D, Karim M, Culley J, Harrison DJ, Hayward L, Langridge-Smith P, Gilbert N, Ramsahoye BH - Nucleic Acids Res. (2012)

HDAC inhibition preferentially up-regulates HDAC-associated genes. (A) The probability of significant gene deregulation in CD4 cells after a 2 h exposure to high-dose butyrate and TSA. (B and C) Analysis of probes with expression values between 1000 and 5000 in CD4 cells. HDAC-associated genes/probes are more likely to be significantly upregulated (B) and less likely to be significantly downregulated (C) when compared with the overall probability of being up or downregulated on the array [horizontal lines (Chi-squared test)]. *P < 0.05; **P < 0.01; ***P < 0.001.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3367171&req=5

gks066-F5: HDAC inhibition preferentially up-regulates HDAC-associated genes. (A) The probability of significant gene deregulation in CD4 cells after a 2 h exposure to high-dose butyrate and TSA. (B and C) Analysis of probes with expression values between 1000 and 5000 in CD4 cells. HDAC-associated genes/probes are more likely to be significantly upregulated (B) and less likely to be significantly downregulated (C) when compared with the overall probability of being up or downregulated on the array [horizontal lines (Chi-squared test)]. *P < 0.05; **P < 0.01; ***P < 0.001.
Mentions: We used t-tests (P < 0.05) to assess significance of deregulation and found that the probability of detecting significant deregulation by HDAC inhibitors varied with the expression values of probes (Figure 5A). The greatest probability of deregulation occurred in probes with expression values between 1000 and 5000 in control cells. A similar pattern was seen with lactate and butyrate on our Illumina expression arrays (Supplementary Figure S2A and B). Interestingly in the Wang et al, dataset genes were more likely to be significantly downregulated than upregulated by HDAC inhibition (Figure 5A). However, when we looked specifically at the genes that were associated with HDAC proteins, we found highly significant effects on gene expression. Genes (probes) with expression values between 1000 and 5000 in control cells were significantly more likely to be upregulated by HDAC inhibition if they were associated with either of the HDACs (Figure 5B). Conversely the probability of being downregulated was less for probes that were associated with each of the HDACs (Figure 5C). Thus, while genes can be both upregulated and downregulated by exposure to HDAC inhibitors, the association of genes with HDAC proteins increases their likelihood of upregulation. This indicates that, rather than controlling the repression of non-expressed genes, HDACs exert a repressive effect on expressed genes and this effect would be modulated by endogenous HDAC inhibitors such as lactate.Figure 5.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XR, SIRCAMS, UK.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus