Elevated Histone Expression Promotes Life Span Extension

Feser, Jason; Truong, David M.; Das, Chandrima; Carson, Joshua J.; Kieft, Jeffrey S.; Harkness, Troy A. A.; Tyler, Jessica K.

doi:10.1016/j.molcel.2010.08.015

Cited by 370 publications

(436 citation statements)

References 62 publications

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“…A reduction in canonical histones has been observed during replicative aging in yeast (44) and in senescent cells in yeast (45) and human fibroblasts (46). Furthermore, in senescent human fibroblasts depletion of canonical histones also is accompanied by an increase in histone H3.3 (47).…”

Section: Discussionmentioning

confidence: 98%

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: 98%

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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“…Chromatin changes during cellular aging are marked by loss of heterochromatin and histone (H1 tail (Funayama, Saito, Tanobe, & Ishikawa, 2006), H3, and H4 (Feser et al, 2010; O'Sullivan, Kubicek, Schreiber, & Karlseder, 2010)) in human cell lines. The overall pattern of histone modifications in aging shows a loss of repressive marks and gain of activating marks (Sen, Shah, Nativio, & Berger, 2016).…”

Section: Molecular Links Between Aging and Admentioning

confidence: 99%

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

et al. 2018

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Alzheimer's disease is the most prevalent cause of dementia, which is defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality proposed by the original amyloid hypothesis. Aging is the main risk factor for Alzheimer's disease that cannot be explained by amyloid hypothesis. To evaluate how aging and Alzheimer's disease are intrinsically interwoven with each other, we review and summarize evidence from molecular, cellular, and system level. In particular, we focus on study designs, treatments, or interventions in Alzheimer's disease that could also be insightful in aging and vice versa.

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“…Despite a clear connection between heterochromatin maintenance and lifespan extension (Feser et al ., 2010; Meister et al ., 2011; Larson et al ., 2012; Jiang et al ., 2013), the cause of heterochromatin loss and how it leads to cellular damage and aging is not well understood. Generally speaking, heterochromatin loss would lead to a mis‐expression of genes that are normally repressed, which could result in age‐ associated cellular defects.…”

Section: Introductionmentioning

confidence: 99%

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

et al. 2016

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SummaryEukaryotic genomes contain transposable elements (TE) that can move into new locations upon activation. Since uncontrolled transposition of TEs, including the retrotransposons and DNA transposons, can lead to DNA breaks and genomic instability, multiple mechanisms, including heterochromatin‐mediated repression, have evolved to repress TE activation. Studies in model organisms have shown that TEs become activated upon aging as a result of age‐associated deregulation of heterochromatin. Considering that different organisms or cell types may undergo distinct heterochromatin changes upon aging, it is important to identify pathways that lead to TE activation in specific tissues and cell types. Through deep sequencing of isolated RNAs, we report an increased expression of many retrotransposons in the old Drosophila fat body, an organ equivalent to the mammalian liver and adipose tissue. This de‐repression correlates with an increased number of DNA damage foci and decreased level of Drosophila lamin‐B in the old fat body cells. Depletion of the Drosophila lamin‐B in the young or larval fat body results in a reduction of heterochromatin and a corresponding increase in retrotransposon expression and DNA damage. Further manipulations of lamin‐B and retrotransposon expression suggest a role of the nuclear lamina in maintaining the genome integrity of the Drosophila fat body by repressing retrotransposons.

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Elevated Histone Expression Promotes Life Span Extension

Cited by 370 publications

References 62 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

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

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