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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

Epileptogenesis: sequence of events, including the role of REST. Causal processes that are possibly involved in the beginning of epileptogenesis are listed in the azure box at the top. Several boxes included in the middle profile (gray) summarize the subsequent events. Hyperexcitability and other structural and functional alterations (top, azure box) are directly connected to the causal processes at the top and to the changes in gene structure/expression of the central box. The appearance of epilepsy, however, is not rapid. Time is needed to convert the first seizures to an enduring process distributed to neuronal circuits. This maturation is not described; instead, it is just mentioned in the thin yellow box at the bottom of the green profile. The gene expression events governed by REST are shown in the two boxes connected to the central box. The blue box to the left includes the predominant genes whose repression promotes epileptogenesis; the clear azure box to the right includes the genes that tend to maintain cell homeostasis and thus to negatively modulate epileptogenesis. The difference in the relevance of the two modulations of REST-dependent genes is illustrated by the different thicknesses of the yellow arrows that receive their modulation. The resulting ongoing epilepsy is indicated in the black box at the bottom.
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Figure 4: Epileptogenesis: sequence of events, including the role of REST. Causal processes that are possibly involved in the beginning of epileptogenesis are listed in the azure box at the top. Several boxes included in the middle profile (gray) summarize the subsequent events. Hyperexcitability and other structural and functional alterations (top, azure box) are directly connected to the causal processes at the top and to the changes in gene structure/expression of the central box. The appearance of epilepsy, however, is not rapid. Time is needed to convert the first seizures to an enduring process distributed to neuronal circuits. This maturation is not described; instead, it is just mentioned in the thin yellow box at the bottom of the green profile. The gene expression events governed by REST are shown in the two boxes connected to the central box. The blue box to the left includes the predominant genes whose repression promotes epileptogenesis; the clear azure box to the right includes the genes that tend to maintain cell homeostasis and thus to negatively modulate epileptogenesis. The difference in the relevance of the two modulations of REST-dependent genes is illustrated by the different thicknesses of the yellow arrows that receive their modulation. The resulting ongoing epilepsy is indicated in the black box at the bottom.

Mentions: In conclusion, the results of studies of the role of REST in epilepsy might appear contradictory. It should be emphasized, however, that conditional deletion of REST before epileptogenesis induces the overexpression of many genes (Hu et al., 2011a; Liu et al., 2012), which may differ in various cell types. In contrast, the protective role of the attenuation of REST activity, as shown by McClelland et al. (2014) after the induction of status epilepticus, clearly documents the participation of increased REST levels in the establishment of the enduring process. This role of REST most likely includes epigenetic effects on many genes with intermediate affinity for the repressor. The overall range of events occurring during epileptogenesis, including the possibly variable role of REST in this process, is illustrated in Figure 4.


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

Baldelli P, Meldolesi J - eNeuro (2015)

Epileptogenesis: sequence of events, including the role of REST. Causal processes that are possibly involved in the beginning of epileptogenesis are listed in the azure box at the top. Several boxes included in the middle profile (gray) summarize the subsequent events. Hyperexcitability and other structural and functional alterations (top, azure box) are directly connected to the causal processes at the top and to the changes in gene structure/expression of the central box. The appearance of epilepsy, however, is not rapid. Time is needed to convert the first seizures to an enduring process distributed to neuronal circuits. This maturation is not described; instead, it is just mentioned in the thin yellow box at the bottom of the green profile. The gene expression events governed by REST are shown in the two boxes connected to the central box. The blue box to the left includes the predominant genes whose repression promotes epileptogenesis; the clear azure box to the right includes the genes that tend to maintain cell homeostasis and thus to negatively modulate epileptogenesis. The difference in the relevance of the two modulations of REST-dependent genes is illustrated by the different thicknesses of the yellow arrows that receive their modulation. The resulting ongoing epilepsy is indicated in the black box at the bottom.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Epileptogenesis: sequence of events, including the role of REST. Causal processes that are possibly involved in the beginning of epileptogenesis are listed in the azure box at the top. Several boxes included in the middle profile (gray) summarize the subsequent events. Hyperexcitability and other structural and functional alterations (top, azure box) are directly connected to the causal processes at the top and to the changes in gene structure/expression of the central box. The appearance of epilepsy, however, is not rapid. Time is needed to convert the first seizures to an enduring process distributed to neuronal circuits. This maturation is not described; instead, it is just mentioned in the thin yellow box at the bottom of the green profile. The gene expression events governed by REST are shown in the two boxes connected to the central box. The blue box to the left includes the predominant genes whose repression promotes epileptogenesis; the clear azure box to the right includes the genes that tend to maintain cell homeostasis and thus to negatively modulate epileptogenesis. The difference in the relevance of the two modulations of REST-dependent genes is illustrated by the different thicknesses of the yellow arrows that receive their modulation. The resulting ongoing epilepsy is indicated in the black box at the bottom.
Mentions: In conclusion, the results of studies of the role of REST in epilepsy might appear contradictory. It should be emphasized, however, that conditional deletion of REST before epileptogenesis induces the overexpression of many genes (Hu et al., 2011a; Liu et al., 2012), which may differ in various cell types. In contrast, the protective role of the attenuation of REST activity, as shown by McClelland et al. (2014) after the induction of status epilepticus, clearly documents the participation of increased REST levels in the establishment of the enduring process. This role of REST most likely includes epigenetic effects on many genes with intermediate affinity for the repressor. The overall range of events occurring during epileptogenesis, including the possibly variable role of REST in this process, is illustrated in Figure 4.

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