Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence

Méndez-Bermúdez, Aarón; Lototska, Liudmyla; Pousse, Mélanie; Tessier, Florent; Croce, Olivier; Latrick, Chrysa M; Cherdyntseva, Veronica; Nassour, Joe; Jiang, Xiaohua; Lu, Yiming; Abbadie, Corinne; Gagos, Sarantis; Ye, Jing; Gilson, Eric

doi:10.1093/nar/gkac603

Cited by 10 publications

(13 citation statements)

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“…Lamin B1 is an important regulator of chromatin architecture and a component of the nuclear lamina whose expression decreased at senescence (Freund et al, 2012;Shimi et al, 2011). Together with the evidence of interactions between TRF2 and Lamin B1 (Pennarun et al, 2021), the fact that senescence-associated TRF2 downregulation reduces the amount of Lamin B1 at heterochromatin (Mendez-Bermudez et al, 2022) suggests a mechanistic link between senescence, TRF2, Lamin B1 and gene expression regulation. Thus, we performed RNA-seq with young (PD 30) MRC-5 cells upon Lamin B1 knock-down and control (Figure S4A).…”

Section: Decreased Lamin B1 Expression Leads To Subtelomeric Gene Der...mentioning

confidence: 96%

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Senescence‐associated transcriptional derepression in subtelomeres is determined in a chromosome‐end‐specific manner

et al. 2023

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Aging is a continuous process leading to physiological deterioration with age. One of the factors contributing to aging is telomere shortening, causing alterations in the protein protective complex named shelterin and replicative senescence. Here, we address the question of the link between this telomere shortening and the transcriptional changes occurring in senescent cells. We found that in replicative senescent cells, the genes whose expression escaped repression are enriched in subtelomeres. The shelterin protein TRF2 and the nuclear lamina factor Lamin B1, both downregulated in senescent cells, are involved in the regulation of some but not all of these subtelomeric genes, suggesting complex mechanisms of transcriptional regulation. Indeed, the subtelomeres containing these derepressed genes are enriched in factors of polycomb repression (EZH2 and H3K27me3), insulation (CTCF and MAZ), and cohesion (RAD21 and SMC3) while being associated with the open A‐type chromatin compartment. These findings unveil that the subtelomere transcriptome associated with senescence is determined in a chromosome‐end‐specific manner according to the type of higher‐order chromatin structure.

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Section: Decreased Lamin B1 Expression Leads To Subtelomeric Gene Der...mentioning

confidence: 96%

“…We asked whether gene expression in subtelomeres can be regulated by the shelterin protein TRF2, which is downregulated as cells approach senescence (Fujita et al, 2010;Mendez-Bermudez et al, 2022) and involved in subtelomeric gene expression (Robin et al, 2014(Robin et al, , 2020.…”

Section: The Shelterin Protein Trf2 Contributes To the Senescence-ass...mentioning

confidence: 99%

Senescence‐associated transcriptional derepression in subtelomeres is determined in a chromosome‐end‐specific manner

et al. 2023

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“…The brain‐isoform PPP2R2C is downregulated in aging brains of wild‐type (WT) and Alzheimer's transgenic mice (Leong et al, 2020). Moreover, it is associated with various mental disorders in humans (Backx et al, 2010; Jacob et al, 2012; Kimura et al, 2019; Xu et al, 2014) and is upregulated by TRF2, which is a telomere capping protein that prevents replicative senescence (Karlseder et al, 2002; Mendez‐Bermudez et al, 2022). Here, we demonstrate in zebrafish and mice that the level of PP2A is reduced in the aged brain.…”

Section: Introductionmentioning

confidence: 99%

Protein phosphatase 2A activators reverse age‐related behavioral changes by targeting neural cell senescence

et al. 2023

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The contribution of cellular senescence to the behavioral changes observed in the elderly remains elusive. Here, we observed that aging is associated with a decline in protein phosphatase 2A (PP2A) activity in the brains of zebrafish and mice. Moreover, drugs activating PP2A reversed age‐related behavioral changes. We developed a transgenic zebrafish model to decrease PP2A activity in the brain through knockout of the ppp2r2c gene encoding a regulatory subunit of PP2A. Mutant fish exhibited the behavioral phenotype observed in old animals and premature accumulation of neural cells positive for markers of cellular senescence, including senescence‐associated β‐galactosidase, elevated levels cdkn2a/b, cdkn1a, senescence‐associated secretory phenotype gene expression, and an increased level of DNA damage signaling. The behavioral and cell senescence phenotypes were reversed in mutant fish through treatment with the senolytic ABT263 or diverse PP2A activators as well as through cdkn1a or tp53 gene ablation. Senomorphic function of PP2A activators was demonstrated in mouse primary neural cells with downregulated Ppp2r2c. We conclude that PP2A reduction leads to neural cell senescence thereby contributing to age‐related behavioral changes and that PP2A activators have senotherapeutic properties against deleterious behavioral effects of brain aging.

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“…Centromeric αSAT (Alpha Satellite) transcripts in particular have been considered vital for kinetochore stabilization and centromere cohesion (Liu et al 2015;McNulty et al 2017;Smurova and De Wulf 2018;Chen et al 2021). The progressive description of pericentromeric HSAT2 and HSAT3 transcripts has elevated their status to essential in several cellular contexts (Eymery et al 2009a), like the formation and regulation of heterochromatin (Saksouk et al 2015;Johnson et al 2017), aging (Enukashvily et al 2007;Mendez-Bermudez et al 2021), response to stress (Jolly et al 2004;Goenka et al 2016;Ninomiya et al 2020), differentiation (Yandım and Karakülah 2019;Dobrynin et al 2020), and cancer (Hall et al 2017;Nogalski and Shenk 2020;Chatterjee and Sengupta 2021).…”

Section: Introductionmentioning

confidence: 99%

Human Satellite 1 (HSAT1) analysis provides novel evidence of pericentromeric transcription

Lopes¹,

Louzada²,

Ferreira³

et al. 2022

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Pericentromeric regions of human chromosomes are composed of tandem-repeated and highly organized sequences named satellite DNAs. Although being known for a long time as the most AT-rich fraction of the human genome, classical satellite HSAT1 has been disregarded in genomic and transcriptional studies, falling behind other human satellites in terms of knowledge. The path followed herein trails with HSAT1 isolation and cloning, followed by in silico analysis. Monomer copy number and expression data was obtained in a wide variety of human cell lines, with greatly varying profiles in tumoral/non-tumoral samples. HSAT1 was mapped in human chromosomes and applied in in situ transcriptional assays. Additionally, it was possible to observe the nuclear organization of HSAT1 transcripts and further characterize them by 3′ RACE-Seq. Size-varying polyadenylated HSAT1 transcripts were detected, which possibly accounts for the intricate regulation of alternative polyadenylation. As far as we know, this work pioneers HSAT1 transcription studies. With the emergence of new human genome assemblies, acrocentric pericentromeres are becoming relevant characters in disease and other biological contexts. HSAT1 sequences and associated noncoding RNAs will most certainly prove significant in the future of HSAT research.

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Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence

Cited by 10 publications

References 48 publications

Senescence‐associated transcriptional derepression in subtelomeres is determined in a chromosome‐end‐specific manner

Senescence‐associated transcriptional derepression in subtelomeres is determined in a chromosome‐end‐specific manner

Protein phosphatase 2A activators reverse age‐related behavioral changes by targeting neural cell senescence

Human Satellite 1 (HSAT1) analysis provides novel evidence of pericentromeric transcription

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