FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence

Macedo, Joana Catarina; Vaz, Sara; Bakker, Björn; Ribeiro, Rui; Bakker, Petra L.; Escandell, José Miguel; Ferreira, Miguel Godinho; Medema, René H.; Foijer, Floris; Logarinho, Elsa

doi:10.1038/s41467-018-05258-6

Cited by 111 publications

(122 citation statements)

References 70 publications

(81 reference statements)

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Section: Foxm1 Regulates the Fate Of Dividing Progenitors During Regementioning

confidence: 99%

“…The regenerating tail is an oxidative environment and we show here that foxm1 expression requires ROS. Furthermore, Foxm1 has been shown to ensure chromosomal stability and genome integrity in U2OS and aged fibroblasts [25,26], raising the intriguing possibility that Foxm1 might ensure that the expansion of the progenitor pool does not lead to genetic instability during regeneration.The expansion of the neural stem cell pool is required for spinal cord regeneration in axolotl, zebrafish and Xenopus [4,8,27]. Here we show that regeneration also requires the precise control of neuronal differentiation.…”

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confidence: 99%

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Foxm1 regulates neuronal progenitor fate during spinal cord regeneration

Pelzer¹,

Phipps

Thuret³

et al. 2020

Preprint

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Keywords: spinal cord / regeneration / Foxm1 / progenitor / Xenopus / differentiation Pelzer et al. Role of Foxm1 during spinal cord regeneration 2 Summary Mammals have limited tissue regeneration capabilities, particularly in the case of the central nervous system. Spinal cord injuries are often irreversible and lead to the loss of motor and sensory function below the site of the damage [1]. In contrast, amphibians suchas Xenopus tadpoles can regenerate a fully functional tail, including their spinal cord, following amputation [2,3]. A hallmark of spinal cord regeneration is the re-activation of Sox2/3+ progenitor cells to promote regrowth of the spinal cord and the generation of new neurons [4,5]. In axolotls, this increase in proliferation is tightly regulated as progenitors switch from a neurogenic to a proliferative division via the planar polarity pathway (PCP) [6][7][8]. How the balance between self-renewal and differentiation is controlled during regeneration is not well understood. Here, we took an unbiased approach to identify regulators of the cell cycle expressed specifically in X.tropicalis spinal cord after tail amputation by RNAseq. This led to the identification of Foxm1 as a potential key transcription factor for spinal cord regeneration. Foxm1-/-X.tropicalis tadpoles develop normally but cannot regenerate their spinal cords. Using single cell RNAseq and immunolabelling, we show that foxm1+ cells in the regenerating spinal cord undergo a transient but dramatic change in the relative length of the different phases of the cell cycle, suggesting a change in their ability to differentiate. Indeed, we show that Foxm1 does not regulate the rate of progenitor proliferation but is required for neuronal differentiation leading to successful spinal cord regeneration. Pelzer et al. Role of Foxm1 during spinal cord regeneration 3 Results Foxm1 is specifically expressed in the regenerating spinal cordWe compared the transcriptome of isolated spinal cords at 1day post amputation (1dpa) and 3dpa to spinal cord from intact tails (0dpa, Figure 1A). Principle component plot, dendogram of sample-to-sample distances and MA-plot of the log fold change (FC) of expression in relation to the average count confirmed the quality of the data (Figures S1A-D). Between 0dpa and 1dpa, 5129 differentially expressed (DE) transcripts (FC> 2 and FDR<0.01) were identified (2074 down-, 3055 up-regulated). Between 0dpa and 3dpa, 9787 genes are differentially expressed (4609 down and 5178 up-regulated, Figure S1E).To identify the most enriched biological processes by gene ontology (GO), a nonbiased hierarchical cluster for all DE genes was performed ( Figure 1B). We observed three phases: first an increase in expression of genes involved in metabolic processes (cluster I), then a strong upregulation of genes associated with cell cycle regulation (cluster II and III) and finally, a downregulation of expression of genes involved in nervous system development (Cluster IV and V, Figure 1B).Using Ingenuity Pathway Analysis (IPA), we identi...

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Section: Foxm1 Regulates the Fate Of Dividing Progenitors During Regementioning

confidence: 99%

mentioning

confidence: 99%

Foxm1 regulates neuronal progenitor fate during spinal cord regeneration

Pelzer¹,

Phipps

Thuret³

et al. 2020

Preprint

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“…FOXM1 also plays an important role in mitotic maintenance, and we observed enriched mitotic expression with FOXM1 depletion. In recent studies, decreased levels of FOXM1 was shown to cause mitotic decline, genomic instability, and senescence during human aging (Macedo et al, 2018). Conversely, FOXM1 overexpression was found to promote mitotic defects and genomic instability (Pfister et al, 2018).…”

Section: Hgsc Tissues and Cells Show Robust Overexpression Of Both Fomentioning

confidence: 99%

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

Barger

Branick

Chee

et al. 2019

Preprint

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We report that the oncogenic transcription factor FOXM1 is arranged in a head-to-head configuration with RHNO1, a gene involved in the ATR/CHK1-dependent DNA replication stress (DRS) response. FOXM1 and RHNO1 are both amplified and upregulated in high-grade serous ovarian cancer (HGSC). FOXM1 and RHNO1 expression are closely associated in normal and cancer tissues, including single cells, and a bidirectional promoter (F/R-BDP) mediates balanced expression. Targeting of FOXM1 and RHNO1 in HGSC cells using shRNA, CRISPR mutagenesis, or CRISPR interference directed to the F/R-BDP reduced DNA homologous recombination repair (HR) capacity, increased DNA damage, reduced clonogenic survival, and sensitized HGSC cells to the poly-ADP ribosylase inhibitor (PARPi) olaparib. Thus, there is functional cooperativity between FOXM1 and RHNO1 in cancer cells, and combinatorial targeting of this bidirectional gene pair may be a novel cancer therapeutic strategy. More broadly, our data provide evidence that bidirectional gene units function in human cancer.Here, we show that FOXM1 and RHNO1 are co-amplified and co-expressed in HGSC, and that their expression in controlled by a bidirectional promoter (named the F/R-BDP). We additionally show that FOXM1 and RHNO1 they cooperatively promote HR, cell survival, and PARPi resistance. Co-regulation and functional cooperativity between FOXM1 and RHNO1 suggests that this bidirectional gene unit is a potential therapeutic target in HGSC and/or other cancers. More generally, our data provide evidence that cooperative bidirectional gene units functionally contribute to cancer. ResultsThe 12p13.33 amplicon contains FOXM1 and RHNO1, co-expressed bidirectional genes FOXM1 is located at 12p13.33, a region with frequent copy number gains in HGSC and several other cancers (Barger et al., 2019;Barger et al., 2015). 12p13.33 amplification was associated with reduced overall survival in HGSC but, unexpectedly, FOXM1 mRNA expression did not (Barger et al., 2015). The 12p13.33 amplicon includes 33 genes (Figure S1). To identify genes at 12p13.33 that might functionally cooperate with FOXM1, we performed expression correlation analyses. FOXM1 expression showed the strongest correlation with RHNO1 expression in HGSC (Figure 1A), pan-cancer (data not shown), and normal human tissues ( Figure S2). In addition, RHNO1 mRNA expression correlated with reduced HGSC survival (data not shown). Genomic analyses of FOXM1 and RHNO1 revealed a head-to-head arrangement with an intervening putative bidirectional promoter (BDP) ( Figure S3). Approximately 10% of human genes are arranged in this manner, and the gene pairs are frequently co-regulated and can function in similar biochemical pathways (Trinklein et al., 2004;Wakano et al., 2012;. The FOXM1/RHNO1 BDP (F/R-BDP) region contains a CpG island (CGI), a common feature of BDPs ( Figure S3) (Antequera, 2003;Takai and Jones, 2004;Wakano et al., 2012).BDPs are often enriched with specific histone modifications H3K4me3, H3K9ac, H3K27ac, and H3K4me2 (Bornelov et al., 20...

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“…Additionally, we found reduced expression of the transcription factor FoxM1 in severely aneuploid cells, whose repression has been recently shown to lead to senescence during aging (225). The polycomb group (PcG) histone H3 lysin-27 methyltransferase EZH2, another down-regulated candidate gene in aneuploidy-induced senescent cells, has been reported to be suppressed in senescent cells and its down-regulation promotes senescence (227).…”

Section: Mild Chromosome Mis-segregation Can Be Tolerated and Propagamentioning

confidence: 70%

“…25A and 25B), leading to our hypothesis that downregulation of FoxM1 might play a role in senescence induction. Interestingly, a recent report studying aneuploidy in the aging context showed FoxM1 repression in aged primary human fibroblasts which exhibited increased chromosome mis-segregation and aneuploidy (225). Importantly, they found that depletion of FoxM1 in young fibroblasts increased mitotic defects and induced senescence, and restoration of FoxM1 in elderly fibroblasts prevented aneuploidy and delayed the onset of senescence, leading to their conclusion that FoxM1 levels regulate aneuploidy and senescence.…”

Section: Activation Of Nf-κb and P38mapk And Potential Candidate Genementioning

confidence: 97%

Chromosomal instability-induced senescence potentiates cell non-autonomous tumourigenic effects

He¹

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FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence

Cited by 111 publications

References 70 publications

Foxm1 regulates neuronal progenitor fate during spinal cord regeneration

Foxm1 regulates neuronal progenitor fate during spinal cord regeneration

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

Chromosomal instability-induced senescence potentiates cell non-autonomous tumourigenic effects

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