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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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DNA hydroxymethylation (5hmC) and methylation (5mC) analyses were performed in the prefrontal cortex of Veh- and NaB-treated FRL and FSL animals. (A) Global 5hmC level was measured using ELISA and showed no significant changes between any of the groups. Data are presented as the average percent of the genomic DNA cytosines that are hydroxymethylated at the 5th carbon. (B) Region-specific 5hmC and 5mC levels were measured at the Bdnf promoter 4 (P4) region, spanning the transcription start site, and data are presented as relative values. FSL-Veh animals had a significant reduction in 5hmC levels at the Bdnf P4 region, and NaB treatment was associated with increased 5hmC levels in the FSL-NaB group. In contrast, 5mC levels at the same locus showed an inverse pattern compared to 5hmC levels, with hypermethylation in FSL-Veh but hypomethylation in the FSL-NaB group. (C) Pearson’s correlation analysis supported an inverse relationship between 5hmC and 5mC level at the Bdnf P4 locus (rho = -0.48; p = 0.045). Data in A and B are presented as group means ± SEM. n = 4–6 animals per group; n = 1 FSL-Veh outlier excluded. *p < 0.05, **p < 0.01.
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Figure 3: DNA hydroxymethylation (5hmC) and methylation (5mC) analyses were performed in the prefrontal cortex of Veh- and NaB-treated FRL and FSL animals. (A) Global 5hmC level was measured using ELISA and showed no significant changes between any of the groups. Data are presented as the average percent of the genomic DNA cytosines that are hydroxymethylated at the 5th carbon. (B) Region-specific 5hmC and 5mC levels were measured at the Bdnf promoter 4 (P4) region, spanning the transcription start site, and data are presented as relative values. FSL-Veh animals had a significant reduction in 5hmC levels at the Bdnf P4 region, and NaB treatment was associated with increased 5hmC levels in the FSL-NaB group. In contrast, 5mC levels at the same locus showed an inverse pattern compared to 5hmC levels, with hypermethylation in FSL-Veh but hypomethylation in the FSL-NaB group. (C) Pearson’s correlation analysis supported an inverse relationship between 5hmC and 5mC level at the Bdnf P4 locus (rho = -0.48; p = 0.045). Data in A and B are presented as group means ± SEM. n = 4–6 animals per group; n = 1 FSL-Veh outlier excluded. *p < 0.05, **p < 0.01.

Mentions: The aberrant levels of TET1 in the prefrontal cortex of FSL-Veh suggested putative changes in DNA hydroxymethylation. However, the assessment of global (genome-wide) 5hmC levels revealed no differences between groups (ANOVA, p = 0.12; Figure 3A). This led us to test the hypothesis that TET1 may affect specific genes. Among the list of candidate genes, we decided to study Bdnf since it is both associated with depression’s pathophysiology and is affected by brain levels of TET1 (Guo et al., 2011; Kaas et al., 2013). In line with our data showing a TET1 downregulation in FSL-Veh, we found a significant reduction in 5hmC levels at the Bdnf P4 locus in this group (ANOVA, p = 0.039; FSL-Veh vs. FRL-Veh, Fisher’s LSD, post hoc p = 0.032; Figure 3B). Interestingly, we also found that the NaB-dependent TET1 overexpression in FSL was associated with higher 5hmC levels at Bdnf P4 (FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.0059; Figure 3B). Next, since hydroxymethylation is considered a mediator of active demethylation in the adult brain (Guo et al., 2011), we also examined the levels of 5mC at the same Bdnf locus. In accord with the decreased 5hmC levels in FSL-Veh, the same group was hypermethylated at Bdnf P4 compared to FRL-Veh (ANOVA, p = 0.023; FSL-Veh vs. FRL-Veh, Fisher’s LSD, post-hoc p = 0.025; Figure 3B). Additionally, the NaB-dependent increase in 5hmC levels in Bdnf P4 of FSL was associated with DNA hypomethylation at the same locus (FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.0035; Figure 3B). Finally, this inverse relationship between 5hmC and 5mC levels at the Bdnf P4 promoter was supported by a correlation analysis (p = 0.045, correlation coefficient = -0.48, Figure 3C).


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)

DNA hydroxymethylation (5hmC) and methylation (5mC) analyses were performed in the prefrontal cortex of Veh- and NaB-treated FRL and FSL animals. (A) Global 5hmC level was measured using ELISA and showed no significant changes between any of the groups. Data are presented as the average percent of the genomic DNA cytosines that are hydroxymethylated at the 5th carbon. (B) Region-specific 5hmC and 5mC levels were measured at the Bdnf promoter 4 (P4) region, spanning the transcription start site, and data are presented as relative values. FSL-Veh animals had a significant reduction in 5hmC levels at the Bdnf P4 region, and NaB treatment was associated with increased 5hmC levels in the FSL-NaB group. In contrast, 5mC levels at the same locus showed an inverse pattern compared to 5hmC levels, with hypermethylation in FSL-Veh but hypomethylation in the FSL-NaB group. (C) Pearson’s correlation analysis supported an inverse relationship between 5hmC and 5mC level at the Bdnf P4 locus (rho = -0.48; p = 0.045). Data in A and B are presented as group means ± SEM. n = 4–6 animals per group; n = 1 FSL-Veh outlier excluded. *p < 0.05, **p < 0.01.
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Figure 3: DNA hydroxymethylation (5hmC) and methylation (5mC) analyses were performed in the prefrontal cortex of Veh- and NaB-treated FRL and FSL animals. (A) Global 5hmC level was measured using ELISA and showed no significant changes between any of the groups. Data are presented as the average percent of the genomic DNA cytosines that are hydroxymethylated at the 5th carbon. (B) Region-specific 5hmC and 5mC levels were measured at the Bdnf promoter 4 (P4) region, spanning the transcription start site, and data are presented as relative values. FSL-Veh animals had a significant reduction in 5hmC levels at the Bdnf P4 region, and NaB treatment was associated with increased 5hmC levels in the FSL-NaB group. In contrast, 5mC levels at the same locus showed an inverse pattern compared to 5hmC levels, with hypermethylation in FSL-Veh but hypomethylation in the FSL-NaB group. (C) Pearson’s correlation analysis supported an inverse relationship between 5hmC and 5mC level at the Bdnf P4 locus (rho = -0.48; p = 0.045). Data in A and B are presented as group means ± SEM. n = 4–6 animals per group; n = 1 FSL-Veh outlier excluded. *p < 0.05, **p < 0.01.
Mentions: The aberrant levels of TET1 in the prefrontal cortex of FSL-Veh suggested putative changes in DNA hydroxymethylation. However, the assessment of global (genome-wide) 5hmC levels revealed no differences between groups (ANOVA, p = 0.12; Figure 3A). This led us to test the hypothesis that TET1 may affect specific genes. Among the list of candidate genes, we decided to study Bdnf since it is both associated with depression’s pathophysiology and is affected by brain levels of TET1 (Guo et al., 2011; Kaas et al., 2013). In line with our data showing a TET1 downregulation in FSL-Veh, we found a significant reduction in 5hmC levels at the Bdnf P4 locus in this group (ANOVA, p = 0.039; FSL-Veh vs. FRL-Veh, Fisher’s LSD, post hoc p = 0.032; Figure 3B). Interestingly, we also found that the NaB-dependent TET1 overexpression in FSL was associated with higher 5hmC levels at Bdnf P4 (FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.0059; Figure 3B). Next, since hydroxymethylation is considered a mediator of active demethylation in the adult brain (Guo et al., 2011), we also examined the levels of 5mC at the same Bdnf locus. In accord with the decreased 5hmC levels in FSL-Veh, the same group was hypermethylated at Bdnf P4 compared to FRL-Veh (ANOVA, p = 0.023; FSL-Veh vs. FRL-Veh, Fisher’s LSD, post-hoc p = 0.025; Figure 3B). Additionally, the NaB-dependent increase in 5hmC levels in Bdnf P4 of FSL was associated with DNA hypomethylation at the same locus (FSL-Veh vs. FSL-NaB, Fisher’s LSD, post-hoc p = 0.0035; Figure 3B). Finally, this inverse relationship between 5hmC and 5mC levels at the Bdnf P4 promoter was supported by a correlation analysis (p = 0.045, correlation coefficient = -0.48, Figure 3C).

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