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. 2011 Jan 21;6(1):e16266.
doi: 10.1371/journal.pone.0016266.

Whole transcriptome sequencing reveals gene expression and splicing differences in brain regions affected by Alzheimer's disease

Natalie A Twine  1 , Karolina Janitz, Marc R Wilkins, Michal Janitz
Affiliations

Whole transcriptome sequencing reveals gene expression and splicing differences in brain regions affected by Alzheimer's disease

Natalie A Twine et al. PLoS One. .

Abstract

Recent studies strongly indicate that aberrations in the control of gene expression might contribute to the initiation and progression of Alzheimer's disease (AD). In particular, alternative splicing has been suggested to play a role in spontaneous cases of AD. Previous transcriptome profiling of AD models and patient samples using microarrays delivered conflicting results. This study provides, for the first time, transcriptomic analysis for distinct regions of the AD brain using RNA-Seq next-generation sequencing technology. Illumina RNA-Seq analysis was used to survey transcriptome profiles from total brain, frontal and temporal lobe of healthy and AD post-mortem tissue. We quantified gene expression levels, splicing isoforms and alternative transcript start sites. Gene Ontology term enrichment analysis revealed an overrepresentation of genes associated with a neuron's cytological structure and synapse function in AD brain samples. Analysis of the temporal lobe with the Cufflinks tool revealed that transcriptional isoforms of the apolipoprotein E gene, APOE-001, -002 and -005, are under the control of different promoters in normal and AD brain tissue. We also observed differing expression levels of APOE-001 and -002 splice variants in the AD temporal lobe. Our results indicate that alternative splicing and promoter usage of the APOE gene in AD brain tissue might reflect the progression of neurodegeneration.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. A transcription profile of normal temporal lobe of the brain for chromosome 1.
The RNASeq read density along the length of the chromosome is shown. The coverage values are measured along intervals of the genome. These intervals vary in size from 1 bp to 10 Mbp depending on how variable the read density is for a particular genomic location. Each bar represents log2 of the frequency reads plotted against chromosome coordinates.
Figure 2
Figure 2. Venn diagram showing distributions of differentially expressed transcripts between healthy and AD brain.
Venn diagram showing the number of differentially expressed transcripts between AD and normal tissue samples across total brain, temporal and frontal lobe. The number of transcripts unique to AD and normal tissues is shown in universe area outside the circles. The numbers of transcripts up-regulated by more than two-fold in AD tissue are indicated in the dark grey circle, while the numbers up-regulated by more than two-fold in normal tissue are highlighted in the light grey circle. The intersection of the two circles refers to number of transcripts which are expressed in both AD and normal tissues but which are less than two-fold different in expression level.
Figure 3
Figure 3. RNA-Seq read mapping to the reference for APOE.
RNA-Seq read mapping to the UCSC reference genome (hg19) of the gene APOE for all 6 samples in this study. The AD tracks are shown in green and normal samples in red. It is clear that the reads map to the 4 exons of the APOE gene as annotated in the UCSC database (APOE exons shown in blue). The absolute read counts for each sample are indicated on the y axis. A schematic representation of the 5 Ensembl transcripts for APOE is shown in brown at the bottom of the figure. N – normal brain samples; AD – Alzheimer's disease brain samples.
Figure 4
Figure 4. Alternative splicing and promoter usage for the APOE gene in temporal lobe tissue.
(a) Transcriptional isoforms APOE-001, APOE-002 and APOE-005 are detected in both normal and AD temporal lobes; APOE-001 and -002 have transcription start site (TSS) A and 005 is initiated at TSS B. Isoform 005 comprises exons 2, 3 and 4 while isoforms 001 and 002 contain all 4 exons. (b) Isoforms 001 and 002 show decreased expression in AD relative to normal temporal lobe, while isoform 005 shows a relative increase in the AD temporal lobe. (c) Relative changes in TSS abundance between normal and AD temporal lobes are indicated by the green/red pie charts, while changes in the two TSS A group isoforms (001 and 002) between normal and AD temporal lobes are shown by the blue/yellow pie charts.
See this image and copyright information in PMC

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