NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence

Parry, Aled; Hoare, Matthew; Bihary, Dóra; Hänsel‐Hertsch, Robert; Smith, Stephen P.; Tomimatsu, Kosuke; Mannion, Elizabeth; Smith, Amy M.; D’Santos, Paula; Russell, I. Alasdair; Balasubramanian, Shankar; Kimurâ, Hiroshi; Samarajiwa, Shamith A.; Narita, Masashi

doi:10.1038/s41467-018-04283-9

Cited by 67 publications

(62 citation statements)

References 78 publications

(119 reference statements)

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“…Secondary senescent cells (mVenus:EV) did not show significant SAHF formation when compared to OIS (p=0.32, Supplementary Fig.3c). This is consistent with previously published data in which impaired Notch signalling partially suppresses SAHF formation in primary senescence context (32). In summary, we show that Notch signalling mediates secondary senescence in vitro.…”

Section: The Transcriptome Of Secondary and A Subset Of Primary Senessupporting

confidence: 94%

Notch signalling mediates secondary senescence

Teo

Rattanavirotkul

Salzano

et al. 2019

Preprint

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Oncogene induced senescence (OIS) is a tumour suppressive response to oncogene activation that can be transmitted to neighbouring cells through secreted factors of the senescence 20 associated secretory phenotype (SASP). Using single-cell transcriptomics we observed two distinct endpoints, a primary marked by Ras and a secondary by Notch. We find that secondary senescence in vitro and in vivo requires Notch, rather than SASP alone as previously thought.Currently, primary and secondary senescent cells are not thought of as functionally distinct endpoints. A blunted SASP response and the induction of fibrillar collagens in secondary 25 senescence compared to OIS point towards a functional diversification.2 One Sentence Summary: Notch signalling is an essential driver of secondary senescence with primary and secondary senescence being distinct molecular endpoints. Main Text:Cellular senescence is a stress response, resulting in a stable cell cycle arrest, and has been 5 implicated in tumour suppression, ageing and wound healing (1-4). Aberrant activation of the Ras oncogene triggers oncogene-induced senescence (OIS), conferring a precancerous state (5,6). OIS is an in vivo tumour suppressor mechanism preventing transformation and halting tumour growth (7,8) with the p53 and Rb/p16 pathways acting as major mediators of senescence induction and maintenance (6,9). OIS is characterised by multiple changes in 10 phenotype, such as heterochromatic foci (9-13) and the senescence-associated secretory phenotype (SASP, 14-16). Through the secretion of extracellular matrix proteases and interleukins and chemokines, OIS cells recruit immune cells, mediating their own clearance. However, SASP has been implicated in cancer initiation (17) by creating an inflammatory pro-tumorigenic microenvironment. Moreover, SASP factors play a role in cellular 15 reprogramming (18,19) and contribute to ageing and tissue degeneration (20-21). SASP acts in a paracrine fashion to induce secondary senescence in surrounding cells and mediates tissue re-organisation. Secondary senescence occurs in cells not directly receiving the stress insult 22 with paracrine secondary senescence being mediated by secreted SASP factors. Paracrine secondary senescence is thought to enhance immune surveillance and to act as a 20 fail-safe mechanism minimising chances of retaining damaged cells (16,22,23). More recently, ectopic Notch pathway activation has been implicated as an intermediate, unstable phenomenon during primary senescence induction, resulting in a distinct secretome.However, Notch as an endpoint for primary senescence and in secondary senescence

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Section: The Transcriptome Of Secondary and A Subset Of Primary Senessupporting

confidence: 94%

Notch signalling mediates secondary senescence

Teo

Rattanavirotkul

Salzano

et al. 2019

Preprint

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“…Interestingly, however, these autonomous and nonautonomous programs appear to be mechanistically linked. While the causal relevance of epigenetic changes during senescence remains elusive, the distinct epigenetic landscape in senescence has been correlated with the SASP (Aird et al 2016;Tasdemir et al 2016;Parry et al 2018). Loss of Lamin B1 appears to orchestrate high-order chromatin structural alterations, genomic instability, and the formation of CCFs, which in turn triggers the SASP (Sadaie et al 2013;Shah et al 2013;Dou et al 2015Dou et al , 2017.…”

Section: Resultsmentioning

confidence: 99%

“…This appears to show a mirror image of the DNA methylation pattern, but whether or not DNA methylation and chromatin accessibility are physically or functionally related has not been tested. In OIS too, a general increase in chromatin accessibility has been reported, and different oncogenes induce different profiles of accessible regions upon senescence entry (Parry et al 2018).…”

Section: Epigeneticsmentioning

confidence: 99%

“…However, emerging evidence indicates that leaked cytoplasmic DNA in turn can also trigger a discrete aspect of senescence, the nonautonomous activity, via activation of the cGAS/STING pathway, which is further discussed in the next section. (Nelson et al 2012;Hoare et al 2016;Ito et al 2017;Parry et al 2018), and secreted extracellular vesicles (Takasugi et al 2017).…”

Section: Chromatin Dynamicsmentioning

confidence: 99%

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Short-term gain, long-term pain: the senescence life cycle and cancer

Chan

Narita

2019

Genes Dev.

Self Cite

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Originally thought of as a stress response end point, the view of cellular senescence has since evolved into one encompassing a wide range of physiological and pathological functions, including both protumorignic and antitumorigenic features. It has also become evident that senescence is a highly dynamic and heterogenous process. Efforts to reconcile the beneficial and detrimental features of senescence suggest that physiological functions require the transient presence of senescent cells in the tissue microenvironment. Here, we propose the concept of a physiological "senescence life cycle," which has pathological consequences if not executed in its entirety.

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“…NOTCH signaling could repress this accessible state at HMGA1 enhancer regions, and presumably shut off HMGA1 expression, while it was not possible to detect similar modifications at the HMGA2 gene. It also turned out that NOTCH was also able to repress chromatin accessibility at most of the sites opened up in RAS-induced senescent cells, and that this effect of NOTCH was very likely due to the suppression of HMGA1 expression [196].…”

Section: Different Transcription Factors Involved In Cell Proliferatimentioning

confidence: 99%

HMGA Genes and Proteins in Development and Evolution

Vignali

Marracci

2020

IJMS

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HMGA (high mobility group A) (HMGA1 and HMGA2) are small non-histone proteins that can bind DNA and modify chromatin state, thus modulating the accessibility of regulatory factors to the DNA and contributing to the overall panorama of gene expression tuning. In general, they are abundantly expressed during embryogenesis, but are downregulated in the adult differentiated tissues. In the present review, we summarize some aspects of their role during development, also dealing with relevant studies that have shed light on their functioning in cell biology and with emerging possible involvement of HMGA1 and HMGA2 in evolutionary biology.

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NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence

Cited by 67 publications

References 78 publications

Notch signalling mediates secondary senescence

Notch signalling mediates secondary senescence

Short-term gain, long-term pain: the senescence life cycle and cancer

HMGA Genes and Proteins in Development and Evolution

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