Molecular turnover, the H3.3 dilemma and organismal aging (hypothesis)

Saade, Evelyne; Pirozhkova, Iryna; Aimbetov, Rakhan; Lipinski, Marc; Ogryzko, Vasily

doi:10.1111/acel.12332

Cited by 13 publications

(7 citation statements)

References 174 publications

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“…H3.3 accumulation was also observed in non-proliferating chicken tissues and senescent human fibroblasts ( 32 , 33 ). In line with these findings, the progressive replacement of H3.1/2 by the H3.3 was hypothesized to constitute a common feature of chromatin organization in postmitotic cells ( 34 ). This hypothesis is particularly intriguing in light of emerging evidence indicating that H3.3 is functionally distinct from its canonical counterparts ( 35 , 36 ).…”

Section: Introductionmentioning

confidence: 72%

Accumulation of histone variant H3.3 with age is associated with profound changes in the histone methylation landscape

Tvardovskiy

Schwämmle

Kempf

et al. 2017

Nucleic Acids Research

101

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Deposition of replication-independent histone variant H3.3 into chromatin is essential for many biological processes, including development and reproduction. Unlike replication-dependent H3.1/2 isoforms, H3.3 is expressed throughout the cell cycle and becomes enriched in postmitotic cells with age. However, lifelong dynamics of H3 variant replacement and the impact of this process on chromatin organization remain largely undefined. Using quantitative middle-down proteomics we demonstrate that H3.3 accumulates to near saturation levels in the chromatin of various mouse somatic tissues by late adulthood. Accumulation of H3.3 is associated with profound changes in global levels of both individual and combinatorial H3 methyl modifications. A subset of these modifications exhibit distinct relative abundances on H3 variants and remain stably enriched on H3.3 throughout the lifespan, suggesting a causal relationship between H3 variant replacement and age-dependent changes in H3 methylation. Furthermore, the H3.3 level is drastically reduced in human hepatocarcinoma cells as compared to nontumoral hepatocytes, suggesting the potential utility of the H3.3 relative abundance as a biomarker of abnormal cell proliferation activity. Overall, our study provides the first quantitative characterization of dynamic changes in H3 proteoforms throughout lifespan in mammals and suggests a role for H3 variant replacement in modulating H3 methylation landscape with age.

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Section: Introductionmentioning

confidence: 72%

Accumulation of histone variant H3.3 with age is associated with profound changes in the histone methylation landscape

Tvardovskiy

Schwämmle

Kempf

et al. 2017

Nucleic Acids Research

101

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“…Despite its connection to gene activity, this histone variant quite counter-intuitively, and like histone H1.0 (see below), accumulates with age—and the rate of accumulation varies between tissues. This is a phenomenon that was described a long time ago [ 9 ], and has only been very recently revisited [ 126 ]. Thus, while in adult mouse thymus, spleen, and intestinal mucosa, H3.2 is the prevalent variant, in kidney and liver, H3.3 is the most abundant.…”

Section: Histone H3 Variants: H33 and Cenh3mentioning

confidence: 99%

The Structural Determinants behind the Epigenetic Role of Histone Variants

Cheema

Ausió

2015

Genes

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Histone variants are an important part of the histone contribution to chromatin epigenetics. In this review, we describe how the known structural differences of these variants from their canonical histone counterparts impart a chromatin signature ultimately responsible for their epigenetic contribution. In terms of the core histones, H2A histone variants are major players while H3 variant CenH3, with a controversial role in the nucleosome conformation, remains the genuine epigenetic histone variant. Linker histone variants (histone H1 family) haven’t often been studied for their role in epigenetics. However, the micro-heterogeneity of the somatic canonical forms of linker histones appears to play an important role in maintaining the cell-differentiated states, while the cell cycle independent linker histone variants are involved in development. A picture starts to emerge in which histone H2A variants, in addition to their individual specific contributions to the nucleosome structure and dynamics, globally impair the accessibility of linker histones to defined chromatin locations and may have important consequences for determining different states of chromatin metabolism.

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“…Because H3.3 accumulates significantly in post-replicative cells, one should expect a critical contribution of H3.3 to age-related changes of chromatin organization and DNA accessibility, with important consequences on organismal aging. Despite the biological relevance of this intriguing possibility, the importance of H3.3 in pro-longevity signaling pathways still remains unaddressed (Saade et al., 2015). Here, we use C. elegans to elucidate the importance of the replication-independent histone variant H3.3 in the context of diverse pro-longevity signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Replication-Independent Histone Variant H3.3 Controls Animal Lifespan through the Regulation of Pro-longevity Transcriptional Programs

et al. 2016

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SummaryChromatin structure orchestrates the accessibility to the genetic material. Replication-independent histone variants control transcriptional plasticity in postmitotic cells. The life-long accumulation of these histones has been described, yet the implications on organismal aging remain elusive. Here, we study the importance of the histone variant H3.3 in Caenorhabditis elegans longevity pathways. We show that H3.3-deficient nematodes have negligible lifespan differences compared to wild-type animals. However, H3.3 is essential for the lifespan extension of C. elegans mutants in which pronounced transcriptional changes control longevity programs. Notably, H3.3 loss critically affects the expression of a very large number of genes in long-lived nematodes, resulting in transcriptional profiles similar to wild-type animals. We conclude that H3.3 positively contributes to diverse lifespan-extending signaling pathways, with potential implications on age-related processes in multicellular organisms.

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Molecular turnover, the H3.3 dilemma and organismal aging (hypothesis)

Cited by 13 publications

References 174 publications

Accumulation of histone variant H3.3 with age is associated with profound changes in the histone methylation landscape

Accumulation of histone variant H3.3 with age is associated with profound changes in the histone methylation landscape

The Structural Determinants behind the Epigenetic Role of Histone Variants

Replication-Independent Histone Variant H3.3 Controls Animal Lifespan through the Regulation of Pro-longevity Transcriptional Programs

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