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Widespread splicing changes in human brain development and aging

ABSTRACT: Differences in transcript splicing are well documented among tissues and between sexes in humans and other organisms. Further, splicing changes in selected genes have been reported in human and mouse brain development. Using high-throughput RNA sequencing we characterized the transcriptome-wide splicing changes occurring over the lifespan in the human brain. We found that in two brain regions, prefrontal cortex and cerebellum, as many as 37% of all expressed protein-coding multi-exon genes undergo significant splicing changes between birth and 98 years of age. Approximately 40% of these changes take place in aging. We confirmed our findings using exon arrays and PCRs and detected identified splicing changes at the protein level. We further associated distinct patterns of age-related splicing changes with expression of the corresponding splicing factors. Thus, splicing plays an important role in shaping the human brain transcriptome in both development and aging.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26586 | GEO | 2013/01/22

SECONDARY ACCESSION(S): PRJNA136479

REPOSITORIES: GEO

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Widespread splicing changes in human brain development and aging

Project description:Differences in transcript splicing are well documented among tissues and between sexes in humans and other organisms. Further, splicing changes in selected genes have been reported in human and mouse brain development. Using high-throughput RNA sequencing we characterized the transcriptome-wide splicing changes occurring over the lifespan in the human brain. We found that in two brain regions, prefrontal cortex and cerebellum, as many as 37% of all expressed protein-coding multi-exon genes undergo significant splicing changes between birth and 98 years of age. Approximately 40% of these changes take place in aging. We confirmed our findings using exon arrays and PCRs and detected identified splicing changes at the protein level. We further associated distinct patterns of age-related splicing changes with expression of the corresponding splicing factors. Thus, splicing plays an important role in shaping the human brain transcriptome in both development and aging. Human post-mortem brain samples from prefrontal cortex and cerebellum from 30 individuals with ages from birth to 100 years were collected. For each five individuals of similar age RNA, extracted from dissected tissue, was pooled resulting in 5 pooled samples. Obtained RNA was hybridized with Affymetrix Human Exon 1.0 ST arrays.

2013-01-22 | E-GEOD-26586 | biostudies-arrayexpress

Widespread regulated alternative splicing of single codons accelerates proteome evolution

Project description:Thousands of human genes contain introns ending in NAGNAG motifs (N any nucleotide), where both NAGs can function as 3' splice sites, yielding isoforms differing by inclusion/exclusion of just three bases. However, the functional importance of NAGNAG alternative splicing is highly controversial. Using very deep RNA-Seq data from sixteen human and eight mouse tissues, we found that approximately half of alternatively spliced NAGNAGs undergo tissue-specific regulation and that regulated events have been selectively retained: alternative splicing of strongly tissue-specific NAGNAGs was ten times as likely to be conserved between species as for non-tissue-specific events. Further, alternative splicing of human NAGNAGs was associated with an order of magnitude increase in the frequency of exon length changes at orthologous mouse/rat exon boundaries, suggesting that NAGNAGs accelerate exon evolution. Together, our analyses show that NAGNAG alternative splicing constitutes a major generator of tissue-specific proteome diversity and accelerates evolution of proteins at exon-exon boundaries.

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The effect of progerin expression on alternative splicing in keratinocytes of HGPS mice

Project description:Exon level expression analysis for the HGPS pathological aging study data set to analyze the effect of progerin expression on alternative splicing in keratinocytes of HGPS mice. Analysis of the effect of pathological aging (transgenic progerin expression) on alternative splicing (AS) using exon microarrays to interrogate the differential exon usage of the entire genome of HGPS mice (postnatal day 24 and 35) and their wild-type litter mates. Our results suggests that early expression of progerin impairs developmental splicing but that as progerin accumulates, the number of genes with AS increases, similar to what is observed in aging wild-type mice. This dataset is one of the 2 datasets in the overall study. An additional data set series is available with exon expression analysis of aging wild-type mice to analyze the effect of age on alternative splicing during physiological aging. The two datasets are linked together in the SuperSeries GSE67289. A link to the SuperSeries is available at the bottom of this page. 16 skin keratinocyte samples from 2 different age groups: postnatal day 24 and postnatal day 35, from 8 HGPS samples and 8 genotype negative (wild-type) littermates.

2015-11-01 | E-GEOD-67288 | biostudies-arrayexpress

Homo sapiens

Project description:Widespread splicing changes in human brain development and aging

| PRJNA136479 | ENA

Widespread regulated alternative splicing of single codons accelerates proteome evolution

2012-01-05 | E-GEOD-30017 | biostudies-arrayexpress

The effect of progerin expression on alternative splicing in keratinocytes of HGPS mice

2015-11-01 | GSE67288 | GEO

The effect of age on alternative splicing in different tissues of wild-type mice

Project description:Exon level expression analysis for the physiological aging study data set to analyze the effect of age on alternative splicing in different tissues and age groups of wild-type mice Analysis of the effect of age on alternative splicing (AS) using exon microarrays to interrogate the differential exon usage of the entire genome of aging wild-type male C57BL/6J mice (4- and 18-month-old) in five tissues (skin, skeletal muscle, bone, thymus, and white adipose tissue) and in an additional 28-month-old age group, which allowed for age-related AS analysis of the skin, skeletal muscle and bone tissues. We found AS genes with age in all tissue, we show that the number of AS genes increased with age and that AS genes across all tissues are involved in RNA processing. Note: This dataset is one of the 2 datasets in the overall study. An additional data set series is available with exon expression analysis of HGPS mice to analyze the effect of progerin expression on alternative splicing. The two datasets are linked together in the SuperSeries GSE67289. A link to the SuperSeries is available at the bottom of this page.

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Influenza virus infection induces widespread alterations of host cell splicing

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2020-08-31 | GSE154596 | GEO

TMT-labeled quantitative protein profiling of hippocampus during human aging

Project description:Human hippocampus is one of the critical brain regions affected by aging. However, a fully understanding of aging-related changes in protein profiles in human hippocampus has not been well described, especially for the Chinese population. With the newly founded human brain bank in Chinese Academy of Medical Sciences & Peking Union Medical College, we performed a 4-plex TMT labeled proteomic study in the hippocampus of postmortem human brains. The ages of death ranged from 22-98, and were grouped into 4 aging groups: 20-50, 50-70, 70-90, and over 90 (n=4 each). None of the donors was diagnosed with neurodegenerative diseases according to their medical history. Our data identified 4582 proteins, among which 99 proteins were upregulated and 42 proteins were downregulated during the aging process.

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