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A role for SUV39H1-mediated H3K9 trimethylation in the control of genome stability and senescence in WI38 human diploid lung fibroblasts.

ABSTRACT: Cellular senescence has been associated with the age-dependent decline in tissue repair and regeneration, the increasing deterioration of the immune system, and the age-dependent increase in the incidence of cancer. Here, we show that senescence of human lung fibroblast WI-38 cells is associated with extensive changes to the gene expression profile, including the differential expression of transcriptional and epigenetic regulators. Among those,SUV39H1 was downregulated in senescent cells, correlated with a decrease in global H3K9 trimethylation, reduced H3K9me3 levels in repetitive DNA sequence regions such as satellites and transposable elements, and increased transcription of these repetitive DNA sequences. This indicates that SUV39H1 plays a role in limiting genomic instability in dividing cells and suggests that SUV39H1 downregulation may contribute to the establishment of senescence by increasing genomic instability. Additionally, the manipulation of SUV39H1 expression levels resulted in altered cell cycle distribution, suggesting a causal role of SUV39H1 in the establishment of cellular senescence. Thus, based on our findings and the results from previous reports, we propose a model in which SUV39H1 downregulation promotes the establishment of cellular senescence.

SUBMITTER: Sidler C

PROVIDER: S-EPMC4153622 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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A role for SUV39H1-mediated H3K9 trimethylation in the control of genome stability and senescence in WI38 human diploid lung fibroblasts.

Sidler Corinne C Woycicki Rafal R Li Dongping D Wang Bo B Kovalchuk Igor I Kovalchuk Olga O

Aging 20140701 7

Cellular senescence has been associated with the age-dependent decline in tissue repair and regeneration, the increasing deterioration of the immune system, and the age-dependent increase in the incidence of cancer. Here, we show that senescence of human lung fibroblast WI-38 cells is associated with extensive changes to the gene expression profile, including the differential expression of transcriptional and epigenetic regulators. Among those,SUV39H1 was downregulated in senescent cells, correl ...[more]

PMID: 25063769

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Project description:In the dentate gyrus of the adult hippocampus new neurons are generated from neural precursor cells through different stages including proliferation and differentiation of neural progenitor cells and maturation of newborn neurons. These stages are controlled by the expression of specific transcription factors and epigenetic mechanisms, which together orchestrate the progression of the neurogenic process. However, little is known about the involvement of histone posttranslational modifications, a crucial epigenetic mechanism in embryonic neurogenesis that regulates fate commitment and neuronal differentiation. During embryonic development, the repressive modification trimethylation of histone H3 on lysine 9 (H3K9me3) contributes to the cellular identity of different cell-types. However, the role of this modification and its H3K9 methyltransferases has not been elucidated in adult hippocampal neurogenesis. We determined that during the stages of neurogenesis in the adult mouse dentate gyrus and in cultured adult hippocampal progenitors (AHPs), there was a dynamic change in the expression and distribution of H3K9me3, being enriched at early stages of the neurogenic process. A similar pattern was observed in the hippocampus for the dimethylation of histone H3 on lysine 9 (H3K9me2), another repressive modification. Among H3K9 methyltransferases, the enzymes Suv39h1 and Suv39h2 exhibited high levels of expression at early stages of neurogenesis and their expression decreased upon differentiation. Pharmacological inhibition of these enzymes by chaetocin in AHPs reduced H3K9me3 and concomitantly decreased neuronal differentiation while increasing proliferation. Moreover, Suv39h1 and Suv39h2 knockdown in newborn cells of the adult mouse dentate gyrus by retrovirus-mediated RNA interference impaired neuronal differentiation of progenitor cells. Our results indicate that H3K9me3 and H3K9 methyltransferases Suv39h1 and Suv39h2 are critically involved in the regulation of adult hippocampal neurogenesis by controlling the differentiation of neural progenitor cells.

Project description:BackgroundCellular senescence can be induced by a variety of extrinsic stimuli, and sustained exposure to sunlight is a key factor in photoaging of the skin. Accordingly, irradiation of skin fibroblasts by UVB light triggers cellular senescence, which is thought to contribute to extrinsic skin aging, although molecular mechanisms are incompletely understood. Here, we addressed molecular mechanisms underlying UVB induced senescence of human diploid fibroblasts.ResultsWe observed a parallel activation of the p53/p21(WAF1) and p16(INK4a)/pRb pathways. Using genome-wide transcriptome analysis, we identified a transcriptional signature of UVB-induced senescence that was conserved in three independent strains of human diploid fibroblasts (HDF) from skin. In parallel, a comprehensive screen for microRNAs regulated during UVB-induced senescence was performed which identified five microRNAs that are significantly regulated during the process. Bioinformatic analysis of miRNA-mRNA networks was performed to identify new functional mRNA targets with high confidence for miR-15a, miR-20a, miR-20b, miR-93, and miR-101. Already known targets of these miRNAs were identified in each case, validating the approach. Several new targets were identified for all of these miRNAs, with the potential to provide new insight in the process of UVB-induced senescence at a genome-wide level. Subsequent analysis was focused on miR-101 and its putative target gene Ezh2. We confirmed that Ezh2 is regulated by miR-101 in human fibroblasts, and found that both overexpression of miR-101 and downregulation of Ezh2 independently induce senescence in the absence of UVB irradiation. However, the downregulation of miR-101 was not sufficient to block the phenotype of UVB-induced senescence, suggesting that other UVB-induced processes induce the senescence response in a pathway redundant with upregulation of miR-101.ConclusionWe performed a comprehensive screen for UVB-regulated microRNAs in human diploid fibroblasts, and identified a network of miRNA-mRNA interactions mediating UVB-induced senescence. In addition, miR-101 and Ezh2 were identified as key players in UVB-induced senescence of HDF.

Dataset Information

A role for SUV39H1-mediated H3K9 trimethylation in the control of genome stability and senescence in WI38 human diploid lung fibroblasts.

Publications

A role for SUV39H1-mediated H3K9 trimethylation in the control of genome stability and senescence in WI38 human diploid lung fibroblasts.

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