Widespread splicing changes in human brain development and aging

Mazin, Pavel; Xiong, Jieyi; Liu, Xiling; Zheng, Yanyan; Zhang, Xiaoyu; Li, Mingshuang; He, Lin; Somel, Mehmet; Yuan, Yuan; Chen, Yi‐Ping Phoebe; Li, Na; Hu, Yuhui; Fu, Ning; Ning, Zhibin; Zeng, Rong; Yang, Hongyi; Chen, Wei; Gelfand, Mikhail S.; Khaitovich, Philipp

doi:10.1038/msb.2012.67

Cited by 194 publications

(207 citation statements)

References 52 publications

(74 reference statements)

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“…It is currently unclear to what extent the transcriptional changes that occur during aging or/and senescence in mammals are a consequence of histone reduction. However, and interestingly, intron retentions are the most abundant age-related splicing changes found in the human brain (48). Therefore, our results prompt us to hypothesize that the splicing alterations found during human aging might be caused by the associated histone depletion.…”

Section: Discussionmentioning

confidence: 82%

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Jimeno-González

Payán-Bravo

Muñoz-Cabello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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RNA polymerase II (RNAPII) transcription elongation is a highly regulated process that greatly influences mRNA levels as well as pre-mRNA splicing. Despite many studies in vitro, how chromatin modulates RNAPII elongation in vivo is still unclear. Here, we show that a decrease in the level of available canonical histones leads to more accessible chromatin with decreased levels of canonical histones and variants H2A.X and H2A.Z and increased levels of H3.3. With this altered chromatin structure, the RNAPII elongation rate increases, and the kinetics of pre-mRNA splicing is delayed with respect to RNAPII elongation. Consistent with the kinetic model of cotranscriptional splicing, the rapid RNAPII elongation induced by histone depletion promotes the skipping of variable exons in the CD44 gene. Indeed, a slowly elongating mutant of RNAPII was able to rescue this defect, indicating that the defective splicing induced by histone depletion is a direct consequence of the increased elongation rate. In addition, genome-wide analysis evidenced that histone reduction promotes widespread alterations in pre-mRNA processing, including intron retention and changes in alternative splicing. Our data demonstrate that premRNA splicing may be regulated by chromatin structure through the modulation of the RNAPII elongation rate. T he transcription process comprises several steps, including preinitiation complex formation, promoter escape, elongation, and termination (1). Recent reports indicate that elongation rates of RNA polymerase II (RNAPII) in mammals range from 0.5 to 4 kb/min, but which factors are responsible for these differences is still unclear (2-4). One obvious candidate for affecting transcription elongation is chromatin structure. The building block of chromatin is the nucleosome comprising 147 bp of DNA around a histone octamer formed by two H2A-H2B dimers and one H3-H4 tetramer. In vitro experiments have demonstrated that nucleosomes are a barrier for RNAPII transcription elongation (5, 6). We have reported that a nucleosome positioned in the body of a transcription unit impairs RNAPII progression in vivo (7). Furthermore, Weber et al. (8) have shown recently that RNAPII stalls in vivo at the entry site of essentially every transcribed nucleosome in Drosophila. Despite this evidence, it is still unclear whether changes in chromatin structure in different regions of a gene or between different genes can regulate the rate of transcription elongation.Transcription and splicing are coupled processes (9, 10). Splicing occurs cotranscriptionally, and multiple lines of evidence indicate that transcription elongation and splicing influence each other. On one hand, it has been suggested that splicing factors are recruited to the template by the transcription machinery (11, 12). On the other hand, the rate of RNAPII elongation influences splicing. The kinetic model proposes that a slow elongation rate facilitates weak splice-site recognition, promoting the inclusion of alternative exons (13, 14). However, recent studies have ex...

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Section: Discussionmentioning

confidence: 82%

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Jimeno-González

Payán-Bravo

Muñoz-Cabello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This trend is evident in both wild‐type mice during physiological aging and in a premature aging mouse model, suggesting that alternative splicing might be more important in the aging process than has previously been noted. Our results are in agreement with those of other recent studies that have shown an effect of age on AS in human brain (Tollervey et al ., 2011; Mazin et al ., 2013), human peripheral blood leukocytes (Harries et al ., 2011), and senescent fibroblasts induced by telomere shortening (Cao et al ., 2011). To our knowledge, this is the first study to show that the amount of age‐related AS increases with more advanced age (4–18 months compared to 4–28 months) and in several tissues.…”

Section: Discussionmentioning

confidence: 99%

“…This result can be compared to that of the Mazin et al . 's (2013) study in human brain using high‐throughput sequencing, which found that nearly 40% of the genes expressed in human brain had changes in splicing over postnatal life. Of these, 70% occurred during development and 30% during aging, and 12% of the total number of genes expressed in the brain had aging‐related splicing (Mazin et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

“…'s (2013) study in human brain using high‐throughput sequencing, which found that nearly 40% of the genes expressed in human brain had changes in splicing over postnatal life. Of these, 70% occurred during development and 30% during aging, and 12% of the total number of genes expressed in the brain had aging‐related splicing (Mazin et al ., 2013). However, when we considered all compared aging periods (and the five tissues), these numbers varied from 0 to 1886 AS genes and were represented by a range between 0 and 30.4% of the total number of genes that were analyzed, which suggests a considerable variability in the number of AS genes between tissues and ages.…”

Section: Discussionmentioning

confidence: 99%

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Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

et al. 2015

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SummaryAlternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome‐wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus, and white adipose tissue from wild‐type C57BL6/J male mice (4 and 18 months old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone, and white adipose tissue between the different age groups (ranging from 27 to 246 AS genes corresponding to 0.3–3.2% of the total number of genes analyzed). For skin, skeletal muscle, and bone, we included a later age group (28 months old) that showed that the number of alternatively spliced genes increased with age in all three tissues (P < 0.01). Analysis of alternatively spliced genes across all tissues by gene ontology and pathway analysis identified 158 genes involved in RNA processing. Additional analysis of AS in a mouse model for the premature aging disease Hutchinson–Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with an impaired developmental splicing. As progerin accumulates, the number of genes with AS increases compared to in wild‐type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known.

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“…Many splicing factors show age‐related changes in their expression that correlate with changes in alternative splicing during aging (Harries et al, 2011; Lee et al, 2016; Mazin et al, 2013; Rodríguez et al, 2016; Tollervey et al, 2011; Wood, Craig, Li, Merry, & Magalhães, 2013). For example, as many as one‐third of all splicing factors exhibit altered expression with age in human blood (Holly et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Proper splicing contributes to visual function in the aging Drosophila eye

et al. 2018

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Changes in splicing patterns are a characteristic of the aging transcriptome; however, it is unclear whether these age‐related changes in splicing facilitate the progressive functional decline that defines aging. In Drosophila, visual behavior declines with age and correlates with altered gene expression in photoreceptors, including downregulation of genes encoding splicing factors. Here, we characterized the significance of these age‐regulated splicing‐associated genes in both splicing and visual function. To do this, we identified differential splicing events in either the entire eye or photoreceptors of young and old flies. Intriguingly, aging photoreceptors show differential splicing of a large number of visual function genes. In addition, as shown previously for aging photoreceptors, aging eyes showed increased accumulation of circular RNAs, which result from noncanonical splicing events. To test whether proper splicing was necessary for visual behavior, we knocked down age‐regulated splicing factors in photoreceptors in young flies and examined phototaxis. Notably, many of the age‐regulated splicing factors tested were necessary for proper visual behavior. In addition, knockdown of individual splicing factors resulted in changes in both alternative splicing at age‐spliced genes and increased accumulation of circular RNAs. Together, these data suggest that cumulative decreases in splicing factor expression could contribute to the differential splicing, circular RNA accumulation, and defective visual behavior observed in aging photoreceptors.

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Widespread splicing changes in human brain development and aging

Abstract: Human brain transcriptome analysis revealed widespread age-related splicing changes in the prefrontal cortex and cerebellum. While most of the splicing changes take place in development, approximately one-third of them extends into aging.

Cited by 194 publications

References 52 publications

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

Proper splicing contributes to visual function in the aging Drosophila eye

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