Senescent cells harbour features of the cancer epigenome

Cruickshanks, Hazel A; McBryan, Tony; Nelson, David M.; VanderKraats, Nathan D.; Shah, Parisha P.; Tuyn, John van; Singh, Taranjit; Brock, Claire; Donahue, Greg; Dunican, Donncha S.; Drotar, Mark E.; Meehan, Richard R.; Edwards, Joanne; Berger, Shelley L.; Adams, Peter D.

doi:10.1038/ncb2879

Cited by 317 publications

(331 citation statements)

References 69 publications

(111 reference statements)

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“…When analyzing the genomic distribution of dmCpGs and, in line with previously published reports (Cruickshanks et al., 2013; Kulis et al., 2012; Yuan et al., 2015), we found that hypomethylated CpGs were enriched at open sea DNA regions, principally intronic and intergenic, irrespective of the type of process. The distribution of hypermethylated CpGs was found to be similar to that of the array, which is to a certain extent to be expected because it was designed to interrogate a promoter‐ and CpG dense‐biased portion of the genome.…”

Section: Discussionmentioning

confidence: 99%

“…While this molecular alteration preferentially occurs at gene bodies, intergenic DNA regions, and repeated DNA elements (Ehrlich, 2009) and is proposed to be associated with chromosomal instability, reactivation of transposable elements, and loss of genomic imprinting, its precise functional role in cancer development is still poorly understood (Rodríguez‐Paredes & Esteller, 2011). Intriguingly, global loss of genomic DNA methylation has also been reported during the aging and senescence process (Cruickshanks et al., 2013; Fraga & Esteller, 2007). Whole‐genome bisulfite sequencing and methylation arrays have confirmed the global loss of DNA methylation in different human tissues including blood (Heyn et al., 2012), mesenchymal stem cells, and brain (Fernández et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

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Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

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SummaryCancer is an aging‐associated disease, but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, the similarity of the regions where this loss of DNA methylation occurs is currently not well characterized, and it is unknown if such regions also share a common chromatin signature in aging and cancer. To address this issue, we analyzed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain, and lung tumors and healthy blood, and integrated the results with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging and 286,746 in cancer. Hyper‐ and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue‐independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, while in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark. Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

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“…We suggest that a reason why transdifferentiation typically fails to shut off an initial genetic program may relate to the failure of resetting heterochromatic domains for new cell type . Understanding how heterochromatic regions are established and maintained will continue to provide insight into enhancing cell conversions and may help explain changes in cell fate in diseases such as cancer (Cruickshanks et al 2013). …”

Section: Repressive Chromatin Features For Pioneer Factor Bindingmentioning

confidence: 99%

Pioneer transcription factors in cell reprogramming

2014

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A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in ''closed'' chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as ''pioneer factors'' to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review.Cell fate control represents the most extreme form of gene regulation. Genes specific to the function of a particular type of cell may be antagonistic to the function of another type of cell, so nature has evolved diverse regulatory mechanisms to ensure stable patterns of gene activation and repression. In prokaryotes, self-sustaining regulatory networks of transcription factors bound to DNA can be sufficient to regulate gene activation and repression (Ptashne 2011). In eukaryotes, ;200-base-pair (bp) segments of the genome are wound nearly twice around an octamer of the four core histones to form nucleosomes, providing steric constraints on how transcription factors can bind DNA (Kornberg and Lorch 1999). As described below, pioneer transcription factors have the special property of being able to overcome such constraints, enabling the factors to engage closed chromatin that is not accessible by other types of transcription factors (Fig. 1). However, further higher-order packaging of nucleosomes into heterochromatin can occlude access to DNA altogether, presenting an additional barrier to cell fate conversion (Fig. 1). This review focuses on the most recent studies of pioneer factors in cell programming and reprogramming, how pioneer factors have special chromatinbinding properties, and facilitators and impediments to chromatin binding. We project that such knowledge will greatly aid future efforts to change the fates of cells at will for research, diagnostic, and therapeutic purposes.

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“…Senescent fibroblasts are known to undergo methylation changes (Cruickshanks et al 2013), and these alterations may lead to epigenetic alterations that promote stochastic changes in gene expression. Alternatively, it has been suggested that DNA damage may modulate gene expression by altering the binding capacity of transcription factors (Rose et al 2012).…”

Section: The Senescent Phenotype and Promiscuous Gene Expressionmentioning

confidence: 99%

Cellular senescence: from growth arrest to immunogenic conversion

Burton

Faragher

2015

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Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a proinflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, wellestablished triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established Batypical^senescent states that may occur independent of DNA damage.

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Senescent cells harbour features of the cancer epigenome

Cited by 317 publications

References 69 publications

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Pioneer transcription factors in cell reprogramming

Cellular senescence: from growth arrest to immunogenic conversion

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