Derepression of BDNF Transcription Involves Calcium-Dependent Phosphorylation of MeCP2

Chen, Wen G.; Chang, Qiang; Lin, Yingxi; Meissner, Alexander; West, Anne E.; Griffith, Eric C.; Jaenisch, Rudolf; Greenberg, Michael E.

doi:10.1126/science.1086446

Cited by 1,141 publications

(1,101 citation statements)

References 36 publications

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“…44 On the other hand, BDNF promoter IV binds the transcriptional repressor, MeCP2 (a methyl-CpG-binding domain protein), in complex with the corepressor sin3a and HDACs. [45][46][47] Inhibition of HDAC by VPA or other inhibitors could cause dissociation of the repressor-corepressor complex from the promoter, resulting in transcriptional disinhibition. It is noteworthy that the antidepressant effect of imipramine is largely reversed by HDAC5 overexpression in the hippocampus of mice subjected to chronic defeat stress, which per se induces downregulation of BDNF III and IV mRNA.…”

Section: Discussionmentioning

confidence: 99%

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

et al. 2007

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Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium-or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium-or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3a or GSK-3b isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.

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Section: Discussionmentioning

confidence: 99%

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

et al. 2007

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“…32 There is therefore an emerging concept for a more gene selective role for MeCP2 involving regulation of a smaller number of key regulatory genes such as brain-derived neurotrophic factor (BDNF), a bona fida MeCP2 target. 33,34 However, this concept does not exclude gene selective or global regulatory functions for MeCP2 in non-neuronal cell types of the fully developed adult. Absence of MeCP2 expression in normal adult human and rodent liver demonstrated in the present study helps to explain the lack of hepatic phenotype for Mecp2 À/À mice.…”

Section: Discussionmentioning

confidence: 99%

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis

et al. 2006

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Myofibroblasts are critical cellular elements of wound healing generated at sites of injury by transdifferentiation of resident cells. A paradigm for this process is conversion of hepatic stellate cells (HSC) into hepatic myofibroblasts. Treatment of HSC with DNA methylation inhibitor 5-aza-2 0 -deoxycytidine (5-azadC) blocked transdifferentiation. 5-azadC also prevented loss of IjBa and PPARc expression that occurs during transdifferentiation to allow acquisition of proinflammatory and profibrogenic characteristics. ChIP analysis revealed IjBa promoter is associated with transcriptionally repressed chromatin that converts to an active state with 5-azadC treatment. The methyl-CpG-binding protein MeCP2 which promotes repressed chromatin structure is selectively detected in myofibroblasts of diseased liver. siRNA knockdown of MeCP2 elevated IjBa promoter activity, mRNA and protein expression in myofibroblasts. MeCP2 interacts with IjBa promoter via a methyl-CpG-dependent mechanism and recruitment into a CBF1 corepression complex. We conclude that MeCP2 and DNA methylation exert epigenetic control over hepatic wound healing and fibrogenesis

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“…15 This does not always preclude a possible effect of environmental factors in discordant phenotypes of MZ twins, since environmental factors may affect the DNA methylation status. [16][17][18] Cause of discordance between MZ twins A number of case reports have revealed that phenotypic discordance between MZ twins can be arisen from several kinds of genetic or epigenetic differences, which are inter-correlated each other. 19 For example, expansion of triplet repeat can alter DNA methylation status, and reduced DNA methylation of transposon can cause transposition and finally causes disruption of a gene.…”

Section: What Is Epigenetics?mentioning

confidence: 99%

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

et al. 2005

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Classical twin research focused on differentiating genetic factors from environmental factors by comparing the concordance rate between monozygotic (MZ) and dizygotic twins. On the other hand, recent twin research tries to identify genetic or epigenetic differences between MZ twins discordant for mental disorders. There are a number of reports of MZ twins discordant for genetic disorders caused by genetic or epigenetic differences of known pathogenic genes. In the case of mental disorder research, for which the causative gene has not been established yet, we are trying to identify the 'pathogenic gene' by comprehensive analysis of genetic or epigenetic difference between discordant MZ twins. To date, no compelling evidence suggesting such difference between MZ twins has been reported. However, if the genetic or epigenetic difference responsible for the discordant phenotype is found, it will have impact on the biology of mental disorder, in which few conclusive molecular genetic evidences have been obtained.

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Derepression of BDNF Transcription Involves Calcium-Dependent Phosphorylation of MeCP2

Cited by 1,141 publications

References 36 publications

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

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