Senescence is a cellular stress response triggered by diverse stressors, including oncogene activation, where it serves as a bona-fide tumour suppressor mechanism. Senescence can be transmitted to ...neighbouring cells, known as paracrine secondary senescence. Secondary senescence was initially described as a paracrine mechanism, but recent evidence suggests a more complex scenario involving juxtacrine communication between cells. In addition, single-cell studies described differences between primary and secondary senescent end-points, which have thus far not been considered functionally distinct. Here we discuss emerging concepts in senescence transmission and heterogeneity in primary and secondary senescence on a cellular and organ level.
Induced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age‐related decline. However, attempts to realize in vivo iPSC ...have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age‐related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e., “younger” cells), rather than dedifferentiation, which bears the risk of cancer? Here, we analyse the dynamics of cellular age during human iPSC reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. We also find that the loss of somatic gene expression and epigenetic age follows different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimized risk of cancer.
Functional heterogeneity in senescence Kirschner, Kristina; Rattanavirotkul, Nattaphong; Quince, Megan F ...
Biochemical Society transactions,
06/2020, Letnik:
48, Številka:
3
Journal Article
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Senescence is a tumour suppressor mechanism which is cell-intrinsically activated in the context of cellular stress. Senescence can further be propagated to neighbouring cells, a process called ...secondary senescence induction. Secondary senescence was initially shown as a paracrine response to the secretion of cytokines from primary senescent cells. More recently, juxtacrine Notch signalling has been implicated in mediating secondary senescence induction. Primary and secondary senescent induction results in distinct transcriptional outcomes. In addition, cell type and the stimulus in which senescence is induced can lead to variations in the phenotype of the senescence response. It is unclear whether heterogeneous senescent end-points are associated with distinct cellular function in situ, presenting functional heterogeneity. Thus, understanding senescence heterogeneity could prove to be important when devising ways of targeting senescent cells by senolytics, senostatics or senogenics. In this review, we discuss a role for functional heterogeneity in senescence in tissue- and cell-type specific manners, highlighting potential differences in senescence outcomes of primary and secondary senescence.
The mouse inner cell mass (ICM) segregates into the epiblast and primitive endoderm (PrE) lineages coincident with implantation of the embryo. The epiblast subsequently undergoes considerable ...expansion of cell numbers prior to gastrulation. To investigate underlying regulatory principles, we performed systematic single-cell RNA sequencing (seq) of conceptuses from E3.5 to E6.5. The epiblast shows reactivation and subsequent inactivation of the X chromosome, with Zfp57 expression associated with reactivation and inactivation together with other candidate regulators. At E6.5, the transition from epiblast to primitive streak is linked with decreased expression of polycomb subunits, suggesting a key regulatory role. Notably, our analyses suggest elevated transcriptional noise at E3.5 and within the non-committed epiblast at E6.5, coinciding with exit from pluripotency. By contrast, E6.5 primitive streak cells became highly synchronized and exhibit a shortened G1 cell-cycle phase, consistent with accelerated proliferation. Our study systematically charts transcriptional noise and uncovers molecular processes associated with early lineage decisions.
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•A high-resolution scRNA-seq map of mouse from peri-implantation to early gastrulation•Symmetry breaking genes and bivalent chromatin are linked to lineage fate at E4.5•X chromosome inactivation correlates with Rlim and anticorrelates with Dnmt3a and Zfp57•Polycomb targets are repressed in the E6.5 epiblast and activated in the primitive streak
Mohammed et al. chart mouse embryonic development from implantation to early gastrulation at single-cell resolution. They describe regulatory processes associated with lineage commitment. An increased level of transcriptional noise is observed prior to lineage commitment, an observation that provides fresh insights into cell fate decision-making processes.
Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow ...cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease.
Integrated droplet- and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney.
A single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses
, before transitioning to become
macrophages that accumulate in late injury. Conversely, a novel
macrophage subset acts during repair.
Complementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.
Ageing is an inevitable condition that afflicts all humans. Recent achievements, such as the generation of induced pluripotent stem cells, have delivered preliminary evidence that slowing down and ...reversing the ageing process might be possible. However, these techniques usually involve complete dedifferentiation, i.e. somatic cell identity is lost as cells are converted to a pluripotent state. Separating the rejuvenative properties of reprogramming from dedifferentiation is a promising prospect, termed epigenetic rejuvenation. Reprogramming-induced rejuvenation strategies currently involve using Yamanaka factors (typically transiently expressed to prevent full dedifferentiation) and are promising candidates to safely reduce biological age. Here, we review the development and potential of reprogramming-induced rejuvenation as an anti-ageing strategy.
Cellular senescence has been implicated in tumor suppression, development, and aging and is accompanied by large-scale chromatin rearrangements, forming senescence-associated heterochromatic foci ...(SAHF). However, how the chromatin is reorganized during SAHF formation is poorly understood. Furthermore, heterochromatin formation in senescence appears to contrast with loss of heterochromatin in Hutchinson-Gilford progeria. We mapped architectural changes in genome organization in cellular senescence using Hi-C. Unexpectedly, we find a dramatic sequence- and lamin-dependent loss of local interactions in heterochromatin. This change in local connectivity resolves the paradox of opposing chromatin changes in senescence and progeria. In addition, we observe a senescence-specific spatial clustering of heterochromatic regions, suggesting a unique second step required for SAHF formation. Comparison of embryonic stem cells (ESCs), somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation.
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•SAHF cells show sequence- and LAD-dependent loss of heterochromatin (HC) structure•Senescence HC behavior is mirrored in Hutchinson-Gilford progeria•Senescence-specific spatial clustering of HC leads to a new model for SAHF formation•Comparing ESCs, somatic, and senescent cells links senescence to differentiation
Chandra, Ewels, et al. map changes in genome organization in cellular senescence using Hi-C. Contrary to the believed increase in heterochromatin in senescence-associated heterochromatic foci formation, they describe a loss of local interactions in heterochromatic regions. This is in agreement with changes observed in progeria cells.
Lamina-associated domains (LADs) cover a large part of the human genome and are thought to play a major role in shaping the nuclear architectural landscape. Here, we perform polymer simulations, ...microscopy, and mass spectrometry to dissect the roles played by heterochromatin- and lamina-mediated interactions in nuclear organization. Our model explains the conventional organization of heterochromatin and euchromatin in growing cells and the pathological organization found in oncogene-induced senescence and progeria. We show that the experimentally observed changes in the locality of contacts in senescent and progeroid cells can be explained as arising due to phase transitions in the system. Within our simulations, LADs are highly stochastic, as in experiments. Our model suggests that, once established, the senescent phenotype should be metastable even if lamina-mediated interactions were reinstated. Overall, our simulations uncover a generic physical mechanism that can regulate heterochromatin segregation and LAD formation in a wide range of mammalian nuclei.
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•A 3D polymer model for heterochromatin and lamina interactions is presented•The model captures chromatin organization in growing, senescent, and progeroid cells•The model explains the change in the chromatin contact network between cell states•The model predicts the stochasticity of lamina contacts and stability of senescence
Chiang et al. use polymer simulations to investigate the roles of heterochromatin and lamina interactions on nuclear reorganization in cellular senescence. Their model captures chromatin organization in growing, senescent, and progeroid cells and predicts that a polymeric phase transition underlies the ensuing rearrangements in the chromatin contact network.
Senescence is a stress-responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin ...into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation and gene regulation during senescence. Genome-wide mapping reveals that LMNB1 is depleted during senescence, preferentially from the central regions of lamina-associated domains (LADs), which are enriched for Lys9 trimethylation on histone H3 (H3K9me3). LMNB1 knockdown facilitates the spatial relocalization of perinuclear H3K9me3-positive heterochromatin, thus promoting SAHF formation, which could be inhibited by ectopic LMNB1 expression. Furthermore, despite the global reduction in LMNB1 protein levels, LMNB1 binding increases during senescence in a small subset of gene-rich regions where H3K27me3 also increases and gene expression becomes repressed. These results suggest that LMNB1 may contribute to senescence in at least two ways due to its uneven genome-wide redistribution: first, through the spatial reorganization of chromatin and, second, through gene repression.
Through the histone methyltransferase EZH2, the Polycomb complex PRC2 mediates H3K27me3 and is associated with transcriptional repression. PRC2 regulates cell-fate decisions in model organisms; ...however, its role in regulating cell differentiation during human embryogenesis is unknown. Here, we report the characterization of EZH2-deficient human embryonic stem cells (hESCs). H3K27me3 was lost upon EZH2 deletion, identifying an essential requirement for EZH2 in methylating H3K27 in hESCs, in contrast to its non-essential role in mouse ESCs. Developmental regulators were derepressed in EZH2-deficient hESCs, and single-cell analysis revealed an unexpected acquisition of lineage-restricted transcriptional programs. EZH2-deficient hESCs show strongly reduced self-renewal and proliferation, thereby identifying a more severe phenotype compared to mouse ESCs. EZH2-deficient hESCs can initiate differentiation toward developmental lineages; however, they cannot fully differentiate into mature specialized tissues. Thus, EZH2 is required for stable ESC self-renewal, regulation of transcriptional programs, and for late-stage differentiation in this model of early human development.
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•Comprehensive examination of EZH2 function in human ESC regulation•EZH2 deficiency causes lineage-restricted derepression of developmental regulators•More severe self-renewal and growth defects in EZH2-deficient hESCs than in mESCs•EZH2-deficient hESCs can differentiate to early lineages but cannot form mature tissues
Collinson et al. use EZH2-deficient human ESCs to demonstrate the broad conservation of Polycomb-group protein function in controlling cell-fate decisions and transcriptional programs during early human development. The authors also uncover unexpected human-specific differences that result in a more severe self-renewal and proliferation phenotype than that of PRC2-deficient mouse ESCs.
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