Epigenetic Regulation of<i>bdnf</i>Gene Transcription in the Consolidation of Fear Memory

Lubin, Farah D.; Roth, Tania L.; Sweatt, J. David

doi:10.1523/jneurosci.1786-08.2008

Cited by 723 publications

(858 citation statements)

References 56 publications

(72 reference statements)

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“…RACK1 Displays a Specific Role in the Regulation of BDNF Exon IV Expression-Because BDNF exons are differentially transcribed upon stimulation (31,(33)(34)(35), we tested whether RACK1 plays a selective role in the regulation of BDNF exon expression. To do so, we measured the mRNA levels of the four major exons of the BDNF gene: I, II, IV, and VI (supplemental Fig.…”

Section: Rack1 Is Required For the Camp-mediated Increase In Bdnfmentioning

confidence: 99%

“…RACK1 Mediates the Dissociation of MeCP2 from BDNF Promoter IV-The activation of BDNF promoter IV can be achieved by chromatin remodeling via the release of the transcription repressor, MeCP2, from the promoter leading to DNA demethylation (34,43). We therefore tested whether nuclear RACK1 up-regulates BDNF expression by promoting the dissociation of MeCP2 from BDNF promoter IV.…”

Section: Rack1 Is Required For the Camp-mediated Increase In Bdnfmentioning

confidence: 99%

“…The expression of each of the eight 5Ј exons is separately controlled by an individual promoter, which is then spliced to the common 3Ј exon that encodes the BDNF protein (28,31). Exon expression is differentially responsive to various types of stimulation (31)(32)(33)(34)(35)(36). For example, exon IV is the major contributor to neuronal activity-dependent BDNF expression (33), and significant increases in the expression of the BDNF IV were observed in the amygdala and hippocampus of rats that had experienced a fear-conditioning paradigm (34,35), whereas the level of BDNF exons I and VI are up-regulated in the hippocampus of rats 2 h after context exposure (34).…”

mentioning

confidence: 99%

“…Exon expression is differentially responsive to various types of stimulation (31)(32)(33)(34)(35)(36). For example, exon IV is the major contributor to neuronal activity-dependent BDNF expression (33), and significant increases in the expression of the BDNF IV were observed in the amygdala and hippocampus of rats that had experienced a fear-conditioning paradigm (34,35), whereas the level of BDNF exons I and VI are up-regulated in the hippocampus of rats 2 h after context exposure (34). Electroconvulsive seizures lead to increases in the expression of BDNF exon II, as well as exon VI, in rat hippocampus (37), and differential expression of BDNF exons was also found during different periods of prefrontal cortex development (38).…”

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confidence: 99%

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Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Neasta

Ron

2010

Journal of Biological Chemistry

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Scaffolding proteins are major contributors to the spatial and temporal orchestration of signaling cascades and hence cellular functions. RACK1 is a scaffolding protein that plays an important role in the regulation of, and cross-talk between, various signaling pathways. Here we report that RACK1 is a mediator of chromatin remodeling, resulting in an exon-specific expression of the brain-derived neurotrophic factor (BDNF) gene. Specifically, we found that following the activation of the cAMP pathway, nuclear RACK1 localizes at the promoter IV region of the BDNF gene by its association with histones H3 and H4, leading to the dissociation of the transcription repressor methyl-CpGbinding protein 2 (MeCP2) from the promoter, resulting in the acetylation of histone H4. These chromatin modifications lead to the activation of the promoter and to the subsequent promoter-controlled transcription of BDNF exon IV. Our findings expand our knowledge regarding the function of scaffolding proteins such as RACK1. Furthermore, this novel mechanism for the regulation of exon-specific expression of the BDNF gene by RACK1 could have implications on the neuronal functions of the growth factor including synaptic plasticity, learning, and memory.Signal transduction cascades are tightly regulated events. Scaffolding proteins play an essential role in the spatial and temporal regulation of individual enzymes and provide the link between extracellular events and intracellular compartments including the nucleus (1). Scaffolding proteins, by means of protein-protein interactions, provide platforms for protein assembly. The scaffolding protein RACK1, which was originally identified as an anchoring protein of protein kinase C ␤II (2), belongs to the WD40 family of proteins characterized by seven WD40 repeats forming a seven-blade ␤-propeller structure (3, 4). This particular structure allows RACK1 to interact with various enzymes including Fyn kinase (5), focal adhesion kinase (6), receptor protein tyrosine phosphatase (7), the cyclic AMP-specific phosphodiesterase (PDE4) isoform PDE4D5 (8), as well as the intracellular tails of receptors such as the insulin-like growth factor 1 receptor (IGF-1R) (9, 10), the inositol 1,4,5-triphosphate receptor (11), and ion channels such as the NR2B subunit of the N-methyl D-aspartate receptors (5). These interactions, and others, put RACK1 at a focal point for spatial and temporal regulation of various signaling cascades. For example, in transformed cultured cancer cells, RACK1 was shown to form a scaffolding complex that includes the IGF-1R, ␤1 integrin, and focal adhesion kinase (6,9,10,12). In addition, RACK1 is also found at the 40 S ribosomal subunit (3,13,14) and was shown to bridge protein kinase C-mediated signaling to the ribosomal translation machinery (15). RACK1 plays an important role in the central nervous system (16). For example, RACK1 links Fyn kinase to its substrate, the NR2B subunit of the N-methyl D-aspartate receptor (5, 17), and contributes to the regulation of channel activity (18)...

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Section: Rack1 Is Required For the Camp-mediated Increase In Bdnfmentioning

confidence: 99%

Section: Rack1 Is Required For the Camp-mediated Increase In Bdnfmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Neasta

Ron

2010

Journal of Biological Chemistry

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“…These events are detectable within 1 h of the experimental intervention. In a further elaboration, Lubin et al (2008) show that in the same gene possessing multiple promoters (ie, Bdnf), behavioral conditioning can induce coordinate changes in both CpG demethylation and increased mRNA expression in a promoter-specific manner. Thus, context alone can demethylate Bdnf exon-promoter I and VI, whereas fear conditioning will demethylate the exonpromoter IV.…”

Section: Cpg Methylation As Cellular Memory: Evidence From Behavioralmentioning

confidence: 93%

CpG Methylation in Neurons: Message, Memory, or Mask?

Sharma

Gavin

Grayson

2010

Neuropsychopharmacol

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The study of CpG methylation of genomic DNA in neurons has emerged from the shadow of cancer biology into a fundamental investigation of neuronal physiology. This advance began with the discovery that catalytic and receptor proteins related to the insertion and recognition of this chemical mark are robustly expressed in neurons. At the smallest scale of analysis is the methylation of a single cytosine base within a regulatory cognate sequence. This singular alteration in a nucleotide can profoundly modify transcription factor binding with a consequent effect on the primary 'transcript'. At the single promoter level, the methylation-demethylation of CpG islands and associated alterations in local chromatin assemblies creates a type of cellular 'memory' capable of long-term regulation of transcription particularly in stages of brain development, differentiation, and maturation. Finally, at the genome-wide scale, methylation studies from post-mortem brains suggest that CpG methylation may serve to cap the genome into active and inactive territories introducing a 'masking' function. This may facilitate rapid DNA-protein interactions by ambient transcriptional proteins onto actively networked gene promoters. Beyond this broad portrayal, there are vast gaps in our understanding of the pathway between neuronal activity and CpG methylation. These include the regulation in post-mitotic neurons of the executor proteins, such as the DNA methyltransferases, the elusive and putative demethylases, and the interactions with histone modifying enzymes.

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Direct Bisulfite Sequencing for Examination of DNA Methylation with Gene and Nucleotide Resolution from Brain Tissues

2012

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DNA methylation is an epigenetic modification that is essential for the development and mature function of the central nervous system. Due to the relevance of this modification in the transcriptional control of gene expression, it is often necessary to examine changes in DNA methylation patterns with both gene and single nucleotide resolution. Here, we describe in depth a basic protocol for direct bisulfite sequencing of DNA isolated from brain tissue, which will permit direct assessment of methylation status at individual genes as well as individual cytosines within a genomic region. This method yields analysis of DNA methylation patterns that are robust, accurate, and reproducible, thereby allowing insights into the role of alterations in DNA methylation in brain tissue.

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Epigenetic Regulation ofbdnfGene Transcription in the Consolidation of Fear Memory

Cited by 723 publications

References 56 publications

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

CpG Methylation in Neurons: Message, Memory, or Mask?

Direct Bisulfite Sequencing for Examination of DNA Methylation with Gene and Nucleotide Resolution from Brain Tissues

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