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Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene.

Wei Y, Melas PA, Wegener G, Mathé AA, Lavebratt C - Int. J. Neuropsychopharmacol. (2014)

Bottom Line: The TET1 upregulation was also associated with an increase of hydroxymethylation and a decrease of methylation in brain-derived neurotrophic factor (Bdnf), a gene associated with neurogenesis and synaptic plasticity.These epigenetic changes were associated with a corresponding BDNF overexpression.Our data support the antidepressant efficacy of HDACis and suggest that their epigenetic effects may also include DNA methylation changes that are mediated by demethylation-facilitating enzymes like TET1.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).

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Gene expression levels of Tet and Dnmt mRNAs were measured in the prefrontal cortex of Veh- and NaB-treated FSL and FRL animals using qRT-PCR. Differences found on the mRNA levels were also tested on the protein levels using the Western blot. (A) Only Tet1 mRNA was differentially expressed between FRL-Veh and FSL-Veh, with reduced levels in the FSL. NaB treatment significantly increased Tet1 mRNA expression in the FSL-NaB group. (B) TET1 protein levels were also reduced in FSL-Veh and were “rescued” in the FSL-NaB animals. (C) Even though Dnmt1 mRNA levels were reduced in the FSL-NaB group, (D) protein measurements of DNMT1 did not reach a statistically significant level of difference. Gene expression data are presented as relative quantifications (R.Q.); two reference genes (Gapdh and Ppia) were used for normalization. Protein data are presented as % of FRL-Veh. Lower panels in (B) and (D) show representative Western blot images of TET1 and DNMT1 from the same gel, respectively, with β-actin as loading control. For each panel (B) and (D), the Western blot images were from the same gel. Data are presented as group means ± SEM. For all figures: n = 5–7 animals per group; n = 1 FSL-Veh outlier excluded. (A) n = 1 FSL-NaB outlier excluded. *p < 0.05, **p < 0.01, ***p < 0.001.
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Figure 2: Gene expression levels of Tet and Dnmt mRNAs were measured in the prefrontal cortex of Veh- and NaB-treated FSL and FRL animals using qRT-PCR. Differences found on the mRNA levels were also tested on the protein levels using the Western blot. (A) Only Tet1 mRNA was differentially expressed between FRL-Veh and FSL-Veh, with reduced levels in the FSL. NaB treatment significantly increased Tet1 mRNA expression in the FSL-NaB group. (B) TET1 protein levels were also reduced in FSL-Veh and were “rescued” in the FSL-NaB animals. (C) Even though Dnmt1 mRNA levels were reduced in the FSL-NaB group, (D) protein measurements of DNMT1 did not reach a statistically significant level of difference. Gene expression data are presented as relative quantifications (R.Q.); two reference genes (Gapdh and Ppia) were used for normalization. Protein data are presented as % of FRL-Veh. Lower panels in (B) and (D) show representative Western blot images of TET1 and DNMT1 from the same gel, respectively, with β-actin as loading control. For each panel (B) and (D), the Western blot images were from the same gel. Data are presented as group means ± SEM. For all figures: n = 5–7 animals per group; n = 1 FSL-Veh outlier excluded. (A) n = 1 FSL-NaB outlier excluded. *p < 0.05, **p < 0.01, ***p < 0.001.

Mentions: Next, in order to address the hypothesis that NaB’s antidepressant-like effects may be related to changes in the expression of enzymes regulating DNA methylation in the prefrontal cortex, we measured mRNA levels of candidate genes involved in DNA hydroxymethylation and methylation (Tet1, Tet2, Tet3, Dnmt1, and Dnmt3a). Among all the candidate genes tested, only Tet1 showed a difference between vehicle-treated FRL and FSL. More specifically, TET1 mRNA levels were decreased in FSL-Veh compared to FRL-Veh (ANOVA, p = 0.0038; FSL-Veh vs. FRL-Veh, Fisher’s LSD, post-hoc p = 0.039; Figure 2A). NaB treatment, which was previously shown to exert antidepressant-like effects, was associated with an upregulation of Tet1 mRNA in the FSL-NaB group (FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.0067; Figure 2A). Western blot experiments confirmed that the Tet1 group-differences observed on the mRNA levels were also present on the protein levels (ANOVA, p = 0.0029; FSL-Veh vs. FRL-Veh, Fisher’s LSD, post-hoc p = 0.0012; FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p < 0.001; Figure 2B). NaB treatment, though less significantly, was also associated with downregulated Dnmt1 mRNA levels in the FSL-NaB group (ANOVA, p = 0.039; FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.014; Figure 2C). However, this difference did not reach significance when measuring the protein levels of DNMT1 (ANOVA, p = 0.84; FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.46; Figure 2D).


Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene.

Wei Y, Melas PA, Wegener G, Mathé AA, Lavebratt C - Int. J. Neuropsychopharmacol. (2014)

Gene expression levels of Tet and Dnmt mRNAs were measured in the prefrontal cortex of Veh- and NaB-treated FSL and FRL animals using qRT-PCR. Differences found on the mRNA levels were also tested on the protein levels using the Western blot. (A) Only Tet1 mRNA was differentially expressed between FRL-Veh and FSL-Veh, with reduced levels in the FSL. NaB treatment significantly increased Tet1 mRNA expression in the FSL-NaB group. (B) TET1 protein levels were also reduced in FSL-Veh and were “rescued” in the FSL-NaB animals. (C) Even though Dnmt1 mRNA levels were reduced in the FSL-NaB group, (D) protein measurements of DNMT1 did not reach a statistically significant level of difference. Gene expression data are presented as relative quantifications (R.Q.); two reference genes (Gapdh and Ppia) were used for normalization. Protein data are presented as % of FRL-Veh. Lower panels in (B) and (D) show representative Western blot images of TET1 and DNMT1 from the same gel, respectively, with β-actin as loading control. For each panel (B) and (D), the Western blot images were from the same gel. Data are presented as group means ± SEM. For all figures: n = 5–7 animals per group; n = 1 FSL-Veh outlier excluded. (A) n = 1 FSL-NaB outlier excluded. *p < 0.05, **p < 0.01, ***p < 0.001.
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Figure 2: Gene expression levels of Tet and Dnmt mRNAs were measured in the prefrontal cortex of Veh- and NaB-treated FSL and FRL animals using qRT-PCR. Differences found on the mRNA levels were also tested on the protein levels using the Western blot. (A) Only Tet1 mRNA was differentially expressed between FRL-Veh and FSL-Veh, with reduced levels in the FSL. NaB treatment significantly increased Tet1 mRNA expression in the FSL-NaB group. (B) TET1 protein levels were also reduced in FSL-Veh and were “rescued” in the FSL-NaB animals. (C) Even though Dnmt1 mRNA levels were reduced in the FSL-NaB group, (D) protein measurements of DNMT1 did not reach a statistically significant level of difference. Gene expression data are presented as relative quantifications (R.Q.); two reference genes (Gapdh and Ppia) were used for normalization. Protein data are presented as % of FRL-Veh. Lower panels in (B) and (D) show representative Western blot images of TET1 and DNMT1 from the same gel, respectively, with β-actin as loading control. For each panel (B) and (D), the Western blot images were from the same gel. Data are presented as group means ± SEM. For all figures: n = 5–7 animals per group; n = 1 FSL-Veh outlier excluded. (A) n = 1 FSL-NaB outlier excluded. *p < 0.05, **p < 0.01, ***p < 0.001.
Mentions: Next, in order to address the hypothesis that NaB’s antidepressant-like effects may be related to changes in the expression of enzymes regulating DNA methylation in the prefrontal cortex, we measured mRNA levels of candidate genes involved in DNA hydroxymethylation and methylation (Tet1, Tet2, Tet3, Dnmt1, and Dnmt3a). Among all the candidate genes tested, only Tet1 showed a difference between vehicle-treated FRL and FSL. More specifically, TET1 mRNA levels were decreased in FSL-Veh compared to FRL-Veh (ANOVA, p = 0.0038; FSL-Veh vs. FRL-Veh, Fisher’s LSD, post-hoc p = 0.039; Figure 2A). NaB treatment, which was previously shown to exert antidepressant-like effects, was associated with an upregulation of Tet1 mRNA in the FSL-NaB group (FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.0067; Figure 2A). Western blot experiments confirmed that the Tet1 group-differences observed on the mRNA levels were also present on the protein levels (ANOVA, p = 0.0029; FSL-Veh vs. FRL-Veh, Fisher’s LSD, post-hoc p = 0.0012; FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p < 0.001; Figure 2B). NaB treatment, though less significantly, was also associated with downregulated Dnmt1 mRNA levels in the FSL-NaB group (ANOVA, p = 0.039; FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.014; Figure 2C). However, this difference did not reach significance when measuring the protein levels of DNMT1 (ANOVA, p = 0.84; FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.46; Figure 2D).

Bottom Line: The TET1 upregulation was also associated with an increase of hydroxymethylation and a decrease of methylation in brain-derived neurotrophic factor (Bdnf), a gene associated with neurogenesis and synaptic plasticity.These epigenetic changes were associated with a corresponding BDNF overexpression.Our data support the antidepressant efficacy of HDACis and suggest that their epigenetic effects may also include DNA methylation changes that are mediated by demethylation-facilitating enzymes like TET1.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).

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Related in: MedlinePlus