Transient forebrain ischemia alters the mRNA expression of methyl DNA-binding factors in the adult rat hippocampus

Jung, Benjamin; Zhang, G; Ho, Warren; Francis, Joseph; Eubanks, James H.

doi:10.1016/s0306-4522(02)00383-4

Cited by 42 publications

(45 citation statements)

References 39 publications

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“…4D). These results are consistent with previous reports that MBDs are expressed predominantly in neurons, and not in glial cells, in the CNS (26). Neurons, but not oligodendrocytes or astrocytes, that have differentiated from AHPs in vitro also express MeCP2 (Fig.…”

Section: Cnssupporting

confidence: 93%

“…As has been observed for fetal NSCs/NPCs and cells differentiated from them (25), we found that in all neural cell types derived from AHPs the region around the gfap transcription initiation site was extensively methylated (Fig. 4A), suggesting that this region is a target for MBD binding in cells expressing MBDs (26) (Fig. 4D) to suppress gfap expression.…”

Section: Cnssupporting

confidence: 78%

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Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain

Kohyama

Kojima

Takatsuka

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Neural stem/progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes, and oligodendrocytes. It has become apparent that intracellular epigenetic modification including DNA methylation, in concert with extracellular cues such as cytokine signaling, is deeply involved in fate specification of NSCs/NPCs by defining cell-type specific gene expression. However, it is still unclear how differentiated neural cells retain their specific attributes by repressing cellular properties characteristic of other lineages. In previous work we have shown that methyl-CpG binding protein transcriptional repressors (MBDs), which are expressed predominantly in neurons in the central nervous system, inhibit astrocyte-specific gene expression by binding to highly methylated regions of their target genes. Here we report that oligodendrocytes, which do not express MBDs, can transdifferentiate into astrocytes both in vitro (cytokine stimulation) and in vivo (ischemic injury) through the activation of the JAK/STAT signaling pathway. These findings suggest that differentiation plasticity in neural cells is regulated by cell-intrinsic epigenetic mechanisms in collaboration with ambient cell-extrinsic cues.glia ͉ JAK/STAT

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Section: Cnssupporting

confidence: 93%

Section: Cnssupporting

confidence: 78%

Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain

Kohyama

Kojima

Takatsuka

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…We did not detect ZBTB4 expression in glial cell populations. The amount of ZBTB4 messenger was highest in the hippocampus, a region that also expresses Mbd1, Mbd2, and MeCP2 (23). Intense staining was also seen in several structures involved in olfaction: the olfactory bulb, piriform cortex, and habenular nuclei.…”

Section: Fig 4 Zbtb4 and Zbtb38mentioning

confidence: 94%

A Family of Human Zinc Finger Proteins That Bind Methylated DNA and Repress Transcription

Filion

Zhenilo

Саложин

et al. 2006

Molecular and Cellular Biology

295

253

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In vertebrates, densely methylated DNA is associated with inactive transcription. Actors in this process include proteins of the MBD family that can recognize methylated CpGs and repress transcription. Kaiso, a structurally unrelated protein, has also been shown to bind methylated CGCGs through its three Krüppel-like C 2 H 2 zinc fingers. The human genome contains two uncharacterized proteins, ZBTB4 and ZBTB38, that contain Kaiso-like zinc fingers. We report that ZBTB4 and ZBTB38 bind methylated DNA in vitro and in vivo. Unlike Kaiso, they can bind single methylated CpGs. When transfected in mouse cells, the proteins colocalize with foci of heavily methylated satellite DNA and become delocalized upon loss of DNA methylation. Chromatin immunoprecipitation suggests that both of these proteins specifically bind to the methylated allele of the H19/Igf2 differentially methylated region. ZBTB4 and ZBTB38 repress the transcription of methylated templates in transfection assays. The two genes have distinct tissue-specific expression patterns, but both are highly expressed in the brain. Our results reveal the existence of a family of Kaiso-like proteins that bind methylated CpGs. Like proteins of the MBD family, they are able to repress transcription in a methyl-dependent manner, yet their tissue-specific expression pattern suggests nonoverlapping functions.

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“…Thus, we do not know for certain whether postmitotic tissues possess the same machinery involved in chromatin organization and demethylation. However, we do know that MBD2/dMTase is expressed in postmitotic tissues such as the brain (35,36) and liver (37). Furthermore, previous studies have demonstrated that VPA can induce both histone acetylation and the expression of methylated genes (reelin, gad67, 5-lipoxygenase) in non-dividing tissues or cells at therapeutically relevant concentrations (8,9).…”

Section: Mbd2/dmtase Is a Demethylase Enzyme Involved In The Active Dmentioning

confidence: 99%

Valproate Induces Replication-independent Active DNA Demethylation

Detich¹,

Bovenzi²,

Szyf

2003

Journal of Biological Chemistry

319

234

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In this report, we demonstrate that valproic acid (VPA), a drug that has been used for decades in the treatment of epilepsy and as a mood stabilizer, triggers replication-independent active demethylation of DNA. Thus, this drug can potentially reverse DNA methylation patterns and erase stable methylation imprints on DNA in non-dividing cells. Recent discoveries support a role for VPA in the regulation of methylated genes; however, the mechanism has been unclear because it is difficult to dissociate active demethylation from the absence of DNA methylation during DNA synthesis. We therefore took advantage of an assay that measures active DNA demethylation independently from other DNA methylation and DNA replication activities in human embryonal kidney 293 cells. We show that VPA induces histone acetylation, DNA demethylation, and expression of an ectopically methylated CMV-GFP plasmid in a dosedependent manner. In contrast, valpromide, an analogue of VPA that does not induce histone acetylation, does not induce demethylation or expression of CMV-GFP. Furthermore, we illustrate that methylated DNAbinding protein 2/DNA demethylase (MBD2/dMTase) participates in this reaction since antisense knockdown of MBD2/dMTase attenuates VPA-induced demethylation. Taken together, our data support a new mechanism of action for VPA as enhancing intracellular demethylase activity through its effects on histone acetylation and raises the possibility that DNA methylation is reversible independent of DNA replication by commonly prescribed drugs.DNA methylation is a modification of DNA whereby methyl groups are added as part of the covalent structure of the genome, thus providing an extra layer of epigenetic information. A well documented relationship exists between DNA methylation, chromatin structure, and gene expression (1) such that methylated genes are generally transcriptionally silent. Two mechanisms have been proposed to explain this repression: the first is that methylation causes interference in the binding of transcription factors and has been shown for several proteins such as AP2 (2) and c-Myc (3). The second mechanism involves the recruitment of various repressor complexes to methylated DNA via the binding of methylated DNA-binding proteins (MBDs). 1 These complexes contain proteins that have histone deacetylase and chromatin remodeling activities, leading to the formation of a more compact and transcriptionally inactive chromatin (4).Valproic acid/Valproate/2-n-propylpentanoic acid (VPA) has been used for decades in the treatment of epilepsy and is also effective as a mood stabilizer and in migraine therapy. Recent data suggest that this drug, in addition to its other known classical actions, can modulate the epigenome by inhibiting histone deacetylases (HDACs) (5, 6), similar to agents such as trichostatin A (TSA) and n-butyrate, thus triggering an increase in gene expression. Other studies also support a role for VPA in the regulation of methylated genes. It was demonstrated that the reelin gene, which encodes a neuron...

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Transient forebrain ischemia alters the mRNA expression of methyl DNA-binding factors in the adult rat hippocampus

Cited by 42 publications

References 39 publications

Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain

Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain

A Family of Human Zinc Finger Proteins That Bind Methylated DNA and Repress Transcription

Valproate Induces Replication-independent Active DNA Demethylation

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