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The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases(1,2,3).

Baldelli P, Meldolesi J - eNeuro (2015)

Bottom Line: Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity.In conclusion, REST is certainly very important in a large number of conditions.We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medicine, University of Genova , 16163 Genova, Italy ; Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia , 16132 Genova, Italy.

ABSTRACT
REST [RE1-silencing transcription factor (also called neuron-restrictive silencer factor)] is known to repress thousands of possible target genes, many of which are neuron specific. To date, REST repression has been investigated mostly in stem cells and differentiating neurons. Current evidence demonstrates its importance in adult neurons as well. Low levels of REST, which are acquired during differentiation, govern the expression of specific neuronal phenotypes. REST-dependent genes encode important targets, including transcription factors, transmitter release proteins, voltage-dependent and receptor channels, and signaling proteins. Additional neuronal properties depend on miRNAs expressed reciprocally to REST and on specific splicing factors. In adult neurons, REST levels are not always low. Increases occur during aging in healthy humans. Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity. Whether neuronal increases in REST are protective or detrimental remains a subject of debate. Examples of CA1 hippocampal neuron protection upon depolarization, and of neurodegeneration upon glutamate treatment and hypoxia have been reported. REST participation in psychiatric and neurological diseases has been shown, especially in Alzheimer's disease and Huntington's disease, as well as epilepsy. Distinct, complex roles of the repressor in these different diseases have emerged. In conclusion, REST is certainly very important in a large number of conditions. We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

No MeSH data available.


Related in: MedlinePlus

REST binding affinity dependence of neuronal gene repression. The figure illustrates the average changes in the repression induced by increases in REST levels in three groups of RE-1-positive genes, which were dependent on their average binding affinity. The genes with high affinity (red) are already 100% repressed at basal levels of REST. The genes with intermediate affinity (green), which are ∼30% repressed at basal levels, exhibit an increase in their repression to ∼80% upon cell treatment with kainate (KA; 6 μm). The low-affinity genes are repressed neither at basal levels nor after KA and would require higher levels of REST to be repressed. The figure is from McClelland et al., 2014.
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Figure 3: REST binding affinity dependence of neuronal gene repression. The figure illustrates the average changes in the repression induced by increases in REST levels in three groups of RE-1-positive genes, which were dependent on their average binding affinity. The genes with high affinity (red) are already 100% repressed at basal levels of REST. The genes with intermediate affinity (green), which are ∼30% repressed at basal levels, exhibit an increase in their repression to ∼80% upon cell treatment with kainate (KA; 6 μm). The low-affinity genes are repressed neither at basal levels nor after KA and would require higher levels of REST to be repressed. The figure is from McClelland et al., 2014.

Mentions: The majority of the studies reported to date have focused on specific processes of REST increases. They demonstrated the relevance of REST and provided information about the mechanisms involved. In these studies, however, comprehensive analysis of the changes in gene expression induced by the increased levels of REST was not performed. Detailed information about this issue was first provided by a recent study performed by McClelland et al. (2014), in which mice were exposed to kainate. In this study, the expression of >400 classic REST gene targets, including the RE-1 sequence in their regulatory domains, was investigated after increases in REST levels of a few fold. The expression of only a relatively small (∼10%) fraction of these genes, characterized by intermediate affinity for the repressor, was found to significantly decrease (McClelland et al., 2014). Analysis of the genes of this fraction revealed that they encode voltage-gated and receptor channels (including, among others, Na+ and K+ channels, glutamatergic receptor subunits, the HCN1 voltage-gated channel, and the Cl− transporter KCC2), together with signaling proteins, some kinases, transcription factors, and a few other proteins (McClelland et al., 2014). The genes with high and low binding affinity, which were already demonstrated to exhibit considerable and minor repression, respectively, before stimulation, were found to undergo no appreciable change after kainate stimulation (Fig. 3). The REST dependence of the results obtained with the various target genes was demonstrated by experiments in which the tone of the repressor was attenuated by the introduction of decoy oligodeoxynucleotides comprised of the RE-1 binding sequence (McClelland et al., 2014). Currently, not all of the genes that modify their expression following stimulation-induced changes in REST may have been identified. Yet, the results of the McClelland et al. (2014) study are expected to have important implications for the interpretation of the REST target gene expression results. It is clear, in fact, that the genes affected by stimulation-induced increases in REST are numerous and that many of them are functionally relevant. At least some of the proteins encoded by these genes could operate not separately but coordinately with each other.


The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases(1,2,3).

Baldelli P, Meldolesi J - eNeuro (2015)

REST binding affinity dependence of neuronal gene repression. The figure illustrates the average changes in the repression induced by increases in REST levels in three groups of RE-1-positive genes, which were dependent on their average binding affinity. The genes with high affinity (red) are already 100% repressed at basal levels of REST. The genes with intermediate affinity (green), which are ∼30% repressed at basal levels, exhibit an increase in their repression to ∼80% upon cell treatment with kainate (KA; 6 μm). The low-affinity genes are repressed neither at basal levels nor after KA and would require higher levels of REST to be repressed. The figure is from McClelland et al., 2014.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596026&req=5

Figure 3: REST binding affinity dependence of neuronal gene repression. The figure illustrates the average changes in the repression induced by increases in REST levels in three groups of RE-1-positive genes, which were dependent on their average binding affinity. The genes with high affinity (red) are already 100% repressed at basal levels of REST. The genes with intermediate affinity (green), which are ∼30% repressed at basal levels, exhibit an increase in their repression to ∼80% upon cell treatment with kainate (KA; 6 μm). The low-affinity genes are repressed neither at basal levels nor after KA and would require higher levels of REST to be repressed. The figure is from McClelland et al., 2014.
Mentions: The majority of the studies reported to date have focused on specific processes of REST increases. They demonstrated the relevance of REST and provided information about the mechanisms involved. In these studies, however, comprehensive analysis of the changes in gene expression induced by the increased levels of REST was not performed. Detailed information about this issue was first provided by a recent study performed by McClelland et al. (2014), in which mice were exposed to kainate. In this study, the expression of >400 classic REST gene targets, including the RE-1 sequence in their regulatory domains, was investigated after increases in REST levels of a few fold. The expression of only a relatively small (∼10%) fraction of these genes, characterized by intermediate affinity for the repressor, was found to significantly decrease (McClelland et al., 2014). Analysis of the genes of this fraction revealed that they encode voltage-gated and receptor channels (including, among others, Na+ and K+ channels, glutamatergic receptor subunits, the HCN1 voltage-gated channel, and the Cl− transporter KCC2), together with signaling proteins, some kinases, transcription factors, and a few other proteins (McClelland et al., 2014). The genes with high and low binding affinity, which were already demonstrated to exhibit considerable and minor repression, respectively, before stimulation, were found to undergo no appreciable change after kainate stimulation (Fig. 3). The REST dependence of the results obtained with the various target genes was demonstrated by experiments in which the tone of the repressor was attenuated by the introduction of decoy oligodeoxynucleotides comprised of the RE-1 binding sequence (McClelland et al., 2014). Currently, not all of the genes that modify their expression following stimulation-induced changes in REST may have been identified. Yet, the results of the McClelland et al. (2014) study are expected to have important implications for the interpretation of the REST target gene expression results. It is clear, in fact, that the genes affected by stimulation-induced increases in REST are numerous and that many of them are functionally relevant. At least some of the proteins encoded by these genes could operate not separately but coordinately with each other.

Bottom Line: Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity.In conclusion, REST is certainly very important in a large number of conditions.We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medicine, University of Genova , 16163 Genova, Italy ; Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia , 16132 Genova, Italy.

ABSTRACT
REST [RE1-silencing transcription factor (also called neuron-restrictive silencer factor)] is known to repress thousands of possible target genes, many of which are neuron specific. To date, REST repression has been investigated mostly in stem cells and differentiating neurons. Current evidence demonstrates its importance in adult neurons as well. Low levels of REST, which are acquired during differentiation, govern the expression of specific neuronal phenotypes. REST-dependent genes encode important targets, including transcription factors, transmitter release proteins, voltage-dependent and receptor channels, and signaling proteins. Additional neuronal properties depend on miRNAs expressed reciprocally to REST and on specific splicing factors. In adult neurons, REST levels are not always low. Increases occur during aging in healthy humans. Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity. Whether neuronal increases in REST are protective or detrimental remains a subject of debate. Examples of CA1 hippocampal neuron protection upon depolarization, and of neurodegeneration upon glutamate treatment and hypoxia have been reported. REST participation in psychiatric and neurological diseases has been shown, especially in Alzheimer's disease and Huntington's disease, as well as epilepsy. Distinct, complex roles of the repressor in these different diseases have emerged. In conclusion, REST is certainly very important in a large number of conditions. We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

No MeSH data available.


Related in: MedlinePlus