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Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity.

Maag JL, Panja D, Sporild I, Patil S, Kaczorowski DC, Bramham CR, Dinger ME, Wibrand K - Front Neurosci (2015)

Bottom Line: Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA.These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements.These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders.

View Article: PubMed Central - PubMed

Affiliation: Genomics and Epigenetics Division, Garvan Institute of Medical Research Sydney, NSW, Australia ; Faculty of Medicine, St Vincent's Clinical School, University of New South Wales Sydney, NSW, Australia.

ABSTRACT
Long-term potentiation (LTP) of synaptic transmission is recognized as a cellular mechanism for learning and memory storage. Although de novo gene transcription is known to be required in the formation of stable LTP, the molecular mechanisms underlying synaptic plasticity remain elusive. Noncoding RNAs have emerged as major regulatory molecules that are abundantly and specifically expressed in the mammalian brain. By combining RNA-seq analysis with LTP induction in the dentate gyrus of live rats, we provide the first global transcriptomic analysis of synaptic plasticity in the adult brain. Expression profiles of mRNAs and long noncoding RNAs (lncRNAs) were obtained at 30 min, 2 and 5 h after high-frequency stimulation of the perforant pathway. The temporal analysis revealed dynamic expression profiles of lncRNAs with many positively, and highly, correlated to protein-coding genes with known roles in synaptic plasticity, suggesting their possible involvement in LTP. In light of observations suggesting a role for retrotransposons in brain function, we examined the expression of various classes of repeat elements. Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA. These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements. These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders.

No MeSH data available.


Related in: MedlinePlus

Novel rat lncRNAs correlated to highly differentially expressed Ensembl genes and Arc mRNA. The Ensembl genes chosen were those with the lowest FDR value for 2 and 5 h (no lncRNAs were identified at 30 min that showed high correlation to any Ensembl genes), and Arc. LncRNA with a neighboring Ensembl gene (from Figure 4C) were excluded from this analysis. The top 5 correlated lncRNAs with a p < 0.05 were plotted. Pearson correlation values are shown to the right of each line. Ensembl genes are colored brown and assigned a Pearson correlation value of 1, while the lncRNA are color-coded in each graph.
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Figure 5: Novel rat lncRNAs correlated to highly differentially expressed Ensembl genes and Arc mRNA. The Ensembl genes chosen were those with the lowest FDR value for 2 and 5 h (no lncRNAs were identified at 30 min that showed high correlation to any Ensembl genes), and Arc. LncRNA with a neighboring Ensembl gene (from Figure 4C) were excluded from this analysis. The top 5 correlated lncRNAs with a p < 0.05 were plotted. Pearson correlation values are shown to the right of each line. Ensembl genes are colored brown and assigned a Pearson correlation value of 1, while the lncRNA are color-coded in each graph.

Mentions: Unlike protein-coding genes, where function can be inferred by identification of known regulatory motifs, structural prediction, or orthology to other genes, there are no established rules for predicting the function of lncRNAs. Based on the premise that genes that show correlated expression profiles may be under a common regulatory architecture and therefore potentially share a common role, we investigated lncRNAs situated in trans relative to the differentially expressed protein-coding genes with focus on lncRNAs correlated to Arc and the most significantly differentially expressed protein-coding genes, Arc, Mapk4, Dbc1, Tet3, Pim1, and Pmepa1 (Figure 5). By applying this method, we found 34 lncRNAs highly correlated (p < 0.05 and Pearson correlation coefficient > 0.75). The corresponding lncRNA include XLOC_047519 corresponding to a lncRNA upstream of Tmem150c (Figure S6A), XLOC_139362 corresponding to the lincRNA Tunar (Figure S6B), and XLOC_055591 corresponding to a lncRNA overlapping, but not sharing any exons with, LOC306079, which does not show any sign of differential expression (Figure S6C). Tunar (TCL1 Upstream Neural Differentiation-Associated RNA), or in human TUNA (Figure S5B), was recently shown to be evolutionary conserved and required for neuronal differentiation (Lin et al., 2014). Deregulation of TUNA in the striatum has been suggested to be part of the pathophysiology of Huntington's disease. The present findings implicate Tunar in neuronal activity-dependent synaptic plasticity in the adult brain, however, these observations need to be tested further. In light of increasing numbers of lncRNAs with demonstrated roles in regulation, we propose that the lncRNAs described in this study may represent important targets for future biological studies in understanding the molecular mechanisms underlying LTP.


Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity.

Maag JL, Panja D, Sporild I, Patil S, Kaczorowski DC, Bramham CR, Dinger ME, Wibrand K - Front Neurosci (2015)

Novel rat lncRNAs correlated to highly differentially expressed Ensembl genes and Arc mRNA. The Ensembl genes chosen were those with the lowest FDR value for 2 and 5 h (no lncRNAs were identified at 30 min that showed high correlation to any Ensembl genes), and Arc. LncRNA with a neighboring Ensembl gene (from Figure 4C) were excluded from this analysis. The top 5 correlated lncRNAs with a p < 0.05 were plotted. Pearson correlation values are shown to the right of each line. Ensembl genes are colored brown and assigned a Pearson correlation value of 1, while the lncRNA are color-coded in each graph.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4589673&req=5

Figure 5: Novel rat lncRNAs correlated to highly differentially expressed Ensembl genes and Arc mRNA. The Ensembl genes chosen were those with the lowest FDR value for 2 and 5 h (no lncRNAs were identified at 30 min that showed high correlation to any Ensembl genes), and Arc. LncRNA with a neighboring Ensembl gene (from Figure 4C) were excluded from this analysis. The top 5 correlated lncRNAs with a p < 0.05 were plotted. Pearson correlation values are shown to the right of each line. Ensembl genes are colored brown and assigned a Pearson correlation value of 1, while the lncRNA are color-coded in each graph.
Mentions: Unlike protein-coding genes, where function can be inferred by identification of known regulatory motifs, structural prediction, or orthology to other genes, there are no established rules for predicting the function of lncRNAs. Based on the premise that genes that show correlated expression profiles may be under a common regulatory architecture and therefore potentially share a common role, we investigated lncRNAs situated in trans relative to the differentially expressed protein-coding genes with focus on lncRNAs correlated to Arc and the most significantly differentially expressed protein-coding genes, Arc, Mapk4, Dbc1, Tet3, Pim1, and Pmepa1 (Figure 5). By applying this method, we found 34 lncRNAs highly correlated (p < 0.05 and Pearson correlation coefficient > 0.75). The corresponding lncRNA include XLOC_047519 corresponding to a lncRNA upstream of Tmem150c (Figure S6A), XLOC_139362 corresponding to the lincRNA Tunar (Figure S6B), and XLOC_055591 corresponding to a lncRNA overlapping, but not sharing any exons with, LOC306079, which does not show any sign of differential expression (Figure S6C). Tunar (TCL1 Upstream Neural Differentiation-Associated RNA), or in human TUNA (Figure S5B), was recently shown to be evolutionary conserved and required for neuronal differentiation (Lin et al., 2014). Deregulation of TUNA in the striatum has been suggested to be part of the pathophysiology of Huntington's disease. The present findings implicate Tunar in neuronal activity-dependent synaptic plasticity in the adult brain, however, these observations need to be tested further. In light of increasing numbers of lncRNAs with demonstrated roles in regulation, we propose that the lncRNAs described in this study may represent important targets for future biological studies in understanding the molecular mechanisms underlying LTP.

Bottom Line: Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA.These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements.These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders.

View Article: PubMed Central - PubMed

Affiliation: Genomics and Epigenetics Division, Garvan Institute of Medical Research Sydney, NSW, Australia ; Faculty of Medicine, St Vincent's Clinical School, University of New South Wales Sydney, NSW, Australia.

ABSTRACT
Long-term potentiation (LTP) of synaptic transmission is recognized as a cellular mechanism for learning and memory storage. Although de novo gene transcription is known to be required in the formation of stable LTP, the molecular mechanisms underlying synaptic plasticity remain elusive. Noncoding RNAs have emerged as major regulatory molecules that are abundantly and specifically expressed in the mammalian brain. By combining RNA-seq analysis with LTP induction in the dentate gyrus of live rats, we provide the first global transcriptomic analysis of synaptic plasticity in the adult brain. Expression profiles of mRNAs and long noncoding RNAs (lncRNAs) were obtained at 30 min, 2 and 5 h after high-frequency stimulation of the perforant pathway. The temporal analysis revealed dynamic expression profiles of lncRNAs with many positively, and highly, correlated to protein-coding genes with known roles in synaptic plasticity, suggesting their possible involvement in LTP. In light of observations suggesting a role for retrotransposons in brain function, we examined the expression of various classes of repeat elements. Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA. These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements. These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders.

No MeSH data available.


Related in: MedlinePlus