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

Piazzesi, Antonia; Papić, Dražen; Bertan, Fabio; Salomoni, Paolo; Nicotera, Pierluigi; Bano, Daniele

doi:10.1016/j.celrep.2016.09.074

Cited by 60 publications

(61 citation statements)

References 39 publications

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“…Together with previous studies ( 31 , 32 , 49 ), our results indicate that progressive age-dependent accumulation of H3.3 variant and consequential loss of canonical H3.1/2 isoforms constitute a conserved feature of chromatin organization in slow and non-dividing cells. Although the physiological relevance of H3 variant replacement with age remains largely undefined, a recent study revealed the essential role of H3.3 in regulating pro-longevity transcriptional programs in C. elegans ( 66 ). Furthermore, lifelong H3.3 turnover was found to be involved in the regulation of neuronal activity-dependent gene expression in mouse brain ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

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

106

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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: Discussionmentioning

confidence: 99%

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

106

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“…Multiple lines of evidence suggest that the respiration rate induces metabolic changes, favoring alternative survival pathways as well as protective homeostatic mechanisms 43 , 53 – 55 . Moreover, mild mitochondrial stress induces the expression of nuclear-encoded genes through epigenetic modifications of chromatin, including posttranslational modification of histones and nucleosome turnover 56 – 59 . Thus, inhibition of mitochondrial respiration can mediate stress response and adaptive processes with a wide array of homeostatic functions 43 , 60 , although the engagement of this complex surveillance pathway is not a predictor of C .…”

Section: Discussionmentioning

confidence: 99%

WAH-1/AIF regulates mitochondrial oxidative phosphorylation in the nematode Caenorhabditis elegans

Troulinaki

Büttner

Cots

et al. 2018

Cell Death Discovery

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Impaired mitochondrial energy metabolism contributes to a wide range of pathologic conditions, including neurodegenerative diseases. Mitochondrial apoptosis-inducing factor (AIF) is required for the correct maintenance of mitochondrial electron transport chain. An emerging body of clinical evidence indicates that several mutations in the AIFM1 gene are causally linked to severe forms of mitochondrial disorders. Here we investigate the consequence of WAH-1/AIF deficiency in the survival of the nematode Caenorhabditis elegans. Moreover, we assess the survival of C. elegans strains expressing a disease-associated WAH-1/AIF variant. We demonstrate that wah-1 downregulation compromises the function of the oxidative phosphorylation system and reduces C. elegans lifespan. Notably, the loss of respiratory subunits induces a nuclear-encoded mitochondrial stress response independently of an evident increase of oxidative stress. Overall, our data pinpoint an evolutionarily conserved role of WAH-1/AIF in the maintenance of proper mitochondrial activity.

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“…It is reported that these alterations are highly related to lamin and chromatin. Therefore, biologists usually label them with fluorescence proteins and use the fluorescence images to study aging [5–8]. …”

Section: Introductionmentioning

confidence: 99%

Segmentation and classification of two-channel C. elegans nucleus-labeled fluorescence images

Zhao

et al. 2017

BMC Bioinformatics

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BackgroundAging is characterized by a gradual breakdown of cellular structures. Nuclear abnormality is a hallmark of progeria in human. Analysis of age-dependent nuclear morphological changes in Caenorhabditis elegans is of great value to aging research, and this calls for an automatic image processing method that is suitable for both normal and abnormal structures.ResultsOur image processing method consists of nuclear segmentation, feature extraction and classification. First, taking up the challenges of defining individual nuclei with fuzzy boundaries or in a clump, we developed an accurate nuclear segmentation method using fused two-channel images with seed-based cluster splitting and k-means algorithm, and achieved a high precision against the manual segmentation results. Next, we extracted three groups of nuclear features, among which five features were selected by minimum Redundancy Maximum Relevance (mRMR) for classifiers. After comparing the classification performances of several popular techniques, we identified that Random Forest, which achieved a mean class accuracy (MCA) of 98.69%, was the best classifier for our data set. Lastly, we demonstrated the method with two quantitative analyses of C. elegans nuclei, which led to the discovery of two possible longevity indicators.ConclusionsWe produced an automatic image processing method for two-channel C. elegans nucleus-labeled fluorescence images. It frees biologists from segmenting and classifying the nuclei manually.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-017-1817-3) contains supplementary material, which is available to authorized users.

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

Cited by 60 publications

References 39 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

WAH-1/AIF regulates mitochondrial oxidative phosphorylation in the nematode Caenorhabditis elegans

Segmentation and classification of two-channel C. elegans nucleus-labeled fluorescence images

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