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De-regulation of gene expression and alternative splicing affects distinct cellular pathways in the aging hippocampus.

Stilling RM, Benito E, Gertig M, Barth J, Capece V, Burkhardt S, Bonn S, Fischer A - Front Cell Neurosci (2014)

Bottom Line: This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing.We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD).This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Göttingen Göttingen, Germany ; Research Group for Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen Göttingen, Germany.

ABSTRACT
Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer's disease (AD). The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD). This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.

No MeSH data available.


Related in: MedlinePlus

RNA editing in the aging hippocampus. (A) Total number of RNA-editing events detectable in the hippocampus of 3-month-old mice and number of changes occurring during aging. (B) Venn diagram showing the overlap of differentially expressed genes, genes affected by splicing and RNA-editing in 24-month-old mice (upper panel) and 29-month-old mice (lower panel). (C) Editing of the pseudogene-transcribed ncRNA Pisd-ps1 within exon 1 was found to be significantly increased in the 29M group (D) Within the well-described editing cassette of the Htr2c mRNA, editing was significantly upregulated at position D (*p < 0.05, n = 3 per group). Error bars indicate s.e.m.
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Figure 5: RNA editing in the aging hippocampus. (A) Total number of RNA-editing events detectable in the hippocampus of 3-month-old mice and number of changes occurring during aging. (B) Venn diagram showing the overlap of differentially expressed genes, genes affected by splicing and RNA-editing in 24-month-old mice (upper panel) and 29-month-old mice (lower panel). (C) Editing of the pseudogene-transcribed ncRNA Pisd-ps1 within exon 1 was found to be significantly increased in the 29M group (D) Within the well-described editing cassette of the Htr2c mRNA, editing was significantly upregulated at position D (*p < 0.05, n = 3 per group). Error bars indicate s.e.m.

Mentions: At 682 of the 17831 known positions, we found RNA-editing in the 3M group (Table S7). Of these 682 positions, we found 14 editing sites in the 24M group and 41 editing sites in 29M that showed significant change in editing frequency, corresponding to 12 and 35 genes, respectively (Figure 5A, Table S8). Interestingly, when we compared genes that undergo altered RNA editing in the aging hippocampus to the list of differentially expressed and spliced genes, there was almost no overlap (Figure 5B) suggesting that gene expression, splicing and RNA editing control distinct cellular pathways in the aging hippocampus. Only one of the genes that was characterized by altered RNA editing in 29-month-old mice was also up-regulated at the gene expression level (Figure 5C). This gene (Pisd-ps1) codes for a non-coding RNA expressed from a pseudogene with unknown function.


De-regulation of gene expression and alternative splicing affects distinct cellular pathways in the aging hippocampus.

Stilling RM, Benito E, Gertig M, Barth J, Capece V, Burkhardt S, Bonn S, Fischer A - Front Cell Neurosci (2014)

RNA editing in the aging hippocampus. (A) Total number of RNA-editing events detectable in the hippocampus of 3-month-old mice and number of changes occurring during aging. (B) Venn diagram showing the overlap of differentially expressed genes, genes affected by splicing and RNA-editing in 24-month-old mice (upper panel) and 29-month-old mice (lower panel). (C) Editing of the pseudogene-transcribed ncRNA Pisd-ps1 within exon 1 was found to be significantly increased in the 29M group (D) Within the well-described editing cassette of the Htr2c mRNA, editing was significantly upregulated at position D (*p < 0.05, n = 3 per group). Error bars indicate s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4230043&req=5

Figure 5: RNA editing in the aging hippocampus. (A) Total number of RNA-editing events detectable in the hippocampus of 3-month-old mice and number of changes occurring during aging. (B) Venn diagram showing the overlap of differentially expressed genes, genes affected by splicing and RNA-editing in 24-month-old mice (upper panel) and 29-month-old mice (lower panel). (C) Editing of the pseudogene-transcribed ncRNA Pisd-ps1 within exon 1 was found to be significantly increased in the 29M group (D) Within the well-described editing cassette of the Htr2c mRNA, editing was significantly upregulated at position D (*p < 0.05, n = 3 per group). Error bars indicate s.e.m.
Mentions: At 682 of the 17831 known positions, we found RNA-editing in the 3M group (Table S7). Of these 682 positions, we found 14 editing sites in the 24M group and 41 editing sites in 29M that showed significant change in editing frequency, corresponding to 12 and 35 genes, respectively (Figure 5A, Table S8). Interestingly, when we compared genes that undergo altered RNA editing in the aging hippocampus to the list of differentially expressed and spliced genes, there was almost no overlap (Figure 5B) suggesting that gene expression, splicing and RNA editing control distinct cellular pathways in the aging hippocampus. Only one of the genes that was characterized by altered RNA editing in 29-month-old mice was also up-regulated at the gene expression level (Figure 5C). This gene (Pisd-ps1) codes for a non-coding RNA expressed from a pseudogene with unknown function.

Bottom Line: This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing.We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD).This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Göttingen Göttingen, Germany ; Research Group for Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen Göttingen, Germany.

ABSTRACT
Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer's disease (AD). The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD). This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.

No MeSH data available.


Related in: MedlinePlus