Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation.

Metsis, Madis; Timmusk, Tõnis; Arenas, Ernest; Persson, Håkan

doi:10.1073/pnas.90.19.8802

Cited by 220 publications

(168 citation statements)

References 48 publications

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“…The activity of specific promoter regions within the bdnf gene dictates the spatial and temporal expression of specific bdnf transcript isoforms (Nanda and Mack, 1998). In addition, neuronal activity has been demonstrated to elicit promoter site-specific transcription initiation from a subset of bdnf promoters in hippocampus (Metsis et al, 1993;Lauterborn et al, 1996;Huang et al, 2002;Rattiner et al, 2004;Tsankova et al, 2004Tsankova et al, , 2006. However, the significance of this differential regulation of bdnf promoters in the adult brain is not completely clear.…”

Section: The Role Of Chromatin-modifying Enzymes In Learning and Memomentioning

confidence: 93%

Epigenetics in the Nervous System: Figure 1.

Jiang¹,

Langley²,

Lubin³

et al. 2008

J. Neurosci.

202

138

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It is becoming increasingly clear that epigenetic modifications are critical factors in the regulation of gene expression. With regard to the nervous system, epigenetic alterations play a role in a diverse set of processes and have been implicated in a variety of disorders. Gaining a more complete understanding of the essential components and underlying mechanisms involved in epigenetic regulation could lead to novel treatments for a number of neurological and psychiatric conditions. Key words: epigenetics; chromatin; DNA methylation; histone; transcription; gene Broadly defined, epigenetics is a type of molecular and cellular "memory" that results in stable changes in gene expression without alterations to the DNA sequence itself. It has long been appreciated that transcription is not occurring on naked DNA, but rather in the context of chromatin which requires the orchestrated effort of not only transcription factors, but also the protein complexes that modify chromatin structure. Currently, commonly studied epigenetic "marks" include DNA methylation and histone modifications, which can include methylation, acetylation, ubiquitination, and phosphorylation, as well as others. Methylation status on any given segment of DNA appears to be controlled in large part by DNA methyltransferases (Ooi and Bestor, 2008). A host of enzymes appear to regulate histone modifications including histone acetyltransferases (HATs) and histone deacetylases (HDACs) as well as methyl-transferases and demethylases (Bhaumik et al., 2007). These epigenetic marks result in alterations to the protein and/or DNA components that make up chromatin structure such that the transcriptional potential of a gene or set of genes near a specific locus is changed. Figure 1 provides an overview of chromatin structure and describes two widely studied epigenetic marks. It is becoming increasingly clear that changes in the chromatin architecture are important factors in gene regulation and understanding these molecular processes and their functional outcomes may give new insight into normal neural function and disease. With regard to brain processes, epigenetic alterations are present and appear to be playing a role in a diverse set of functions including learning and memory processes, drug addiction, neurodegeneration, and circadian rhythms. Epigenetic mechanisms have been implicated in specific human disorders including Fragile X syndrome, Rett syndrome, Huntington's disease, schizophrenia, and bipolar disorder. Understanding the molecular components and environmental conditions that cause or result in epigenetic changes may provide unique opportunities to develop novel interventions and therapies to treat a variety of neurological and psychiatric conditions. The role of chromatin-modifying enzymes in learning and memory processesThe role of transcription in long-lasting forms of synaptic plasticity and memory has been actively investigated since initial experiments showing that transcription is required for long-term memory in goldfish nearly 40 years ...

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Section: The Role Of Chromatin-modifying Enzymes In Learning and Memomentioning

confidence: 93%

Epigenetics in the Nervous System: Figure 1.

Jiang¹,

Langley²,

Lubin³

et al. 2008

J. Neurosci.

202

138

View full text Add to dashboard Cite

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“…1 A). Upstream of the noncoding exons are promoters governing differential mechanisms of activation and tissue-specific transcript expression in the CNS (Ohara et al, 1992;Metsis et al, 1993;Kokaia et al, 1994;Timmusk et al, 1995). In AD, BDNF transcripts I, II, and IV are specifically decreased (Garzon et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

Garzon¹,

Fahnestock²

2007

J. Neurosci.

171

127

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Alzheimer's disease (AD) is a senile dementia characterized by amyloid plaques, neurofibrillary tangles, and synaptic and cell loss. The "amyloid cascade" hypothesis suggests that amyloid-␤ (A␤), the peptide deposited as amyloid plaques, is the primary insult in AD. However, debate continues over the mechanism of A␤ toxicity and whether fibrillar or oligomeric A␤ is the active species of the peptide that ultimately causes the synaptic loss and dementia associated with AD. Brain-derived neurotrophic factor (BDNF) is required for survival and function of cells compromised in AD. Decreased BDNF causes defects in long-term potentiation and memory and correlates with cognitive decline. We previously demonstrated that BDNF reduction occurs early in the course of AD, suggesting that decreased BDNF may promote neuronal dysfunction in AD. We also demonstrated that three of seven human BDNF transcripts are specifically downregulated in AD. What pathological feature(s) of AD leads to the decreased BDNF is unknown.In this study, we administered both fibrillar and oligomeric conformations of A␤ 1-42 to differentiated SH-SY5Y, a human neuroblastoma cell line, and measured both phosphorylated cAMP response element-binding protein (CREB), a regulator of BDNF transcription, and BDNF total mRNA. We found that oligomeric but not fibrillar preparations of A␤ 1-42 significantly decrease both phosphorylated CREB and total BDNF mRNA. Furthermore, oligomeric A␤ 1-42 decreases BDNF transcripts IV and V in these cells, demonstrating that A␤ 1-42 downregulates the major BDNF transcript decreased in vivo in the AD brain. Thus, oligomeric A␤ 1-42 could compromise neuronal function, causing memory loss and cognitive dysfunction by downregulation of BDNF in AD.

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“…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%

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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Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation.

Cited by 220 publications

References 48 publications

Epigenetics in the Nervous System: Figure 1.

Epigenetics in the Nervous System: Figure 1.

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

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