SnapShot: Cellular Senescence in Pathophysiology.

Cellular senescence is a fundamental cell fate, important both in physiological and pathophysiological processes. This SnapShot focuses on the role of cellular senescence in health, disease, and aging.

SnapShot: Cellular Senescence Pathways.

Cellular senescence is a fundamental cell fate, playing important physiological and pathophysiological roles. This SnapShot focuses on major signaling pathways and transcriptional control mechanisms that consolidate the senescence phenotype.

MicroRNAs and lncRNAs in senescence: A re-view.

Cellular senescence is a stress response to a variety of extrinsic and intrinsic insults that cause genomic or epigenomic perturbations. It is now widely recognized as a potent tumor suppressor mechanism as well as a biological process impacting aging and organismal development. Like other cell fate decisions, senescence is executed and maintained by an intricate network of transcription factors (TFs), chromatin modifiers, and noncoding RNAs (ncRNAs). Altogether, these factors cooperate to implement the gene expression program that initiates and sustains the senescent phenotype. In the context of senescence, microRNAs (miRs) and long ncRNAs have been found to play regulatory roles at both the transcriptional and post-transcriptional levels. In this review, we discuss recent developments in the field and point toward future research directions to gain a better understanding of ncRNAs in senescence.

Escape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars.

Although oncogene-induced senescence (OIS) is a potent tumor-suppressor mechanism, recent studies revealed that cells could escape from OIS with features of transformed cells. However, the mechanisms that promote OIS escape remain unclear, and evidence of post-senescent cells in human cancers is missing. Here, we unravel the regulatory mechanisms underlying OIS escape using dynamic multidimensional profiling. We demonstrate a critical role for AP1 and POU2F2 transcription factors in escape from OIS and identify senescence-associated chromatin scars (SACSs) as an epigenetic memory of OIS detectable during colorectal cancer progression. POU2F2 levels are already elevated in precancerous lesions and as cells escape from OIS, and its expression and binding activity to cis-regulatory elements are associated with decreased patient survival. Our results support a model in which POU2F2 exploits a precoded enhancer landscape necessary for senescence escape and reveal POU2F2 and SACS gene signatures as valuable biomarkers with diagnostic and prognostic potential.

Author Correction: AP-1 imprints a reversible transcriptional programme of senescent cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

AP-1 imprints a reversible transcriptional programme of senescent cells.

Senescent cells affect many physiological and pathophysiological processes. While select genetic and epigenetic elements for senescence induction have been identified, the dynamics, epigenetic mechanisms and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding the deliberate therapeutic targeting of senescence for health benefits. Here, we examined the possibility that the epigenetic state of enhancers determines senescent cell fate. We explored this by generating time-resolved transcriptomes and epigenome profiles during oncogenic RAS-induced senescence and validating central findings in different cell biology and disease models of senescence. Through integrative analysis and functional validation, we reveal links between enhancer chromatin, transcription factor recruitment and senescence competence. We demonstrate that activator protein 1 (AP-1) 'pioneers' the senescence enhancer landscape and defines the organizational principles of the transcription factor network that drives the transcriptional programme of senescent cells. Together, our findings enabled us to manipulate the senescence phenotype with potential therapeutic implications.

RETRACTED: USP1 Regulates Cellular Senescence by Controlling Genomic Integrity.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors. We, the authors, were made aware of irregularities associated in western blots shown in our article. We have further investigated the matter and found that the paper contains multiple examples of incorrect data use and image flipping in four figures, including the vertical flipping and reuse of the panel in Figures 1B and 3D, similar flipping and incorrect blot image in Figure 2C, and incorrect data use in Figure 4A. All of these figures were assembled by the corresponding author (O.B.) who takes full responsibility for the inaccuracies. Under these circumstances, we believe that the most responsible course of action is to retract the paper. We sincerely apologize to the scientific community for any inconvenience resulting from the publication and retraction of this manuscript.

PARP1 enhances inflammatory cytokine expression by alteration of promoter chromatin structure in microglia.

BACKGROUND: Poly(ADP-ribose) polymerase 1 (PARP1) is a chromatin-associated enzyme that participates in processes such as transcription and DNA repair through the regulation of chromatin structure. Accumulating evidence suggests an important role for PARP1 enzymatic activity in promoting CNS inflammation by facilitating the expression of inflammatory cytokines in glial cells. However, the molecular mechanisms by which PARP1 enzymatic activity mediates this process are not well understood. In this report we sought to determine the molecular mechanisms by which PARP1 enzymatic activity facilitates the expression of Il1ß and TNF in LPS-stimulated BV2 cells. METHODS: PARP1 enzymatic activity and histone ADP-ribosylation were measured in LPS-stimulated BV2 cells by radioactive labelling with (32)P-NAD(+). To assess the effect of histone ADP-ribosylation on nucleosome structure, in vitro nucleosome remodeling, nuclease accessibility and binding assays were performed. These studies were complemented by chromatin immunoprecipitation assays in resting and LPS-stimulated BV2 cells in order to determine the occupancy of PARP1, nucleosomes and the RelA subunit of NF-κB, as well as ADP-ribosylation, at the Il1ß and Tnf promoters. Finally, we determined the effect of pharmacological inhibition of PARP1 enzymatic activity on the LPS stimulation-dependent induction of Il1ß and Tnf mRNA. RESULTS: Our results indicate that LPS stimulation induces PARP1 enzymatic activity and histone ADP-ribosylation in the chromatin compartment of BV2 cells. In vitro studies show that nucleosome-bound PARP1 disrupts nucleosome structure histone ADP-ribosylation, increasing the accessibility of nucleosomal DNA. Consistent with this PARP1 is constitutively associated with at the Il1ß and Tnf promoters in resting BV2 cells. Upon stimulation with LPS, ADP-ribosylation is observed at these promoters, and this is correlated with increased recruitment of the transcription factor NF-κB, resulting in robust transcription of these inflammatory cytokines. Accordingly, pharmacological inhibition of PARP1 enzymatic activity reduces NF-κB recruitment, and Il1ß and Tnf expression in LPS-stimulated microglia. CONCLUSIONS: Collectively, our data suggest that PARP1 facilitates inflammatory cytokine expression in microglia by increasing the accessibility of promoter DNA via histone ADP-riboyslation.