The heterogeneity of cellular senescence: insights at the single-cell level

Cohn, Rachel; Gasek, Nathan S.; Kuchel, George A.; Xu, Ming

doi:10.1016/j.tcb.2022.04.011

Cited by 137 publications

(93 citation statements)

References 45 publications

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“…To our knowledge, this study presents the first depiction of the senescence phenotype at the single cell multiomic level (scRNA + scATAC). We believe our characterized gene and enhancer signatures will help pave the way toward a universal marker set of senescence, which is currently outstanding (Cohn et al, 2022; Gorgoulis et al, 2019). Using these single-cell senescent profiles along with their eGRN signatures, we can already show here a close proximity between the senescence phenotype and oncogenic programs, mostly due to the shared upregulation of C/EBP transcription factors activity.…”

Section: Discussionmentioning

confidence: 99%

Shared enhancer gene regulatory networks between wound and oncogenic programs

Floc’hlay

Balaji

Christiaens

et al. 2022

Preprint

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Wound response programs are often activated during neoplastic growth in tumors. In both wound repair and tumor growth, cells respond to acute stress and balance the activation of multiple programs including apoptosis, proliferation, and cell migration. Central to those responses are the activation of the JNK/MAPK and JAK/STAT signaling pathways. Yet, to what extent these signaling cascades interact at the cis-regulatory level, and how they orchestrate different regulatory and phenotypic responses is still unclear. Here, we aim to characterize the regulatory states that emerge and cooperate in the wound response, using the Drosophila melanogaster wing disc as a model system, and compare these with cancer cell states induced by rasV12scrib-/- in the eye disc. We used single-cell multiome profiling to derive enhancer Gene Regulatory Networks (eGRNs) by integrating chromatin accessibility and gene expression signals. We identify a proliferative eGRN, active in the majority of wounded cells and controlled by AP-1 and STAT. In a smaller, but distinct population of wound cells, a senescent eGRN is activated and driven by C/EBP-like transcription factors (Irbp18, Xrp1, Slow border, and Vrille) and Scalloped. In tumor cells on the other hand, both eGRN signatures are simultaneously active within the same cell. Our single-cell multiome and eGRNs resource offers an in-depth characterisation of the senescence markers, together with a new perspective on the shared gene regulatory programs acting during wound response and oncogenesis.

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Section: Discussionmentioning

confidence: 99%

Shared enhancer gene regulatory networks between wound and oncogenic programs

Floc’hlay

Balaji

Christiaens

et al. 2022

Preprint

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“…The generation of additional reporters into different loci, e.g. cdkn2a/b or other senescent markers will also allow to address the possible heterogeneity of senescent cells 46 .…”

Section: Discussionmentioning

confidence: 99%

Generation of a transparent killifish line through multiplex CRISPR/Cas9-mediated gene inactivation

Krug

Albertz

Hopfenmueller

et al. 2022

Preprint

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Body pigmentation is a major limitation for in vivo imaging and thus for the performance of longitudinal studies in biomedicine. A possibility to circumvent this obstacle is the employment of pigmentation mutants, which are used in fish species like zebrafish and medaka. To address the molecular basis of aging, the short-lived African killifish Nothobranchius furzeri has recently been established as a model organism. Despite its short lifespan, N. furzeri shows typical signs of mammalian aging including telomere shortening, accumulation of senescent cells and loss of regenerative capacity. Here, we report the generation of a transparent N. furzeri line by simultaneous inactivation of three key loci responsible for pigmentation. We demonstrate that this stable line, named klara, can serve as a tool for different in vivo applications including behavioral experiments addressing mate choice and the establishment of a senescence reporter by homology-directed repair-mediated integration of a fluorophore into the cdkn1a (p21) locus.

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“…Heterogeneity in the behavior and response of cancer cells is now well established (Dagogo-Jack & Shaw, 2018; Melo, Vermeulen, Fessler, & Medema, 2013), and recent work indicates a similar heterogeneity is present within senescent cells (Cohn, Gasek, Kuchel, & Xu, 2022). In this regard, it is interesting that we observed heterogeneity in the proliferative response of U2OS and OVCAR-8 cells following JNK and Mek inhibition in response to treatment with 0.5 µM doxorubicin, with only a fraction of the inhibitor-treated cells escaping from senescence onset.…”

Section: Discussionmentioning

confidence: 99%

Biphasic JNK–Erk Signaling Separates Induction and Maintenance of Cell Senescence after DNA Damage

Netterfield

Ostheimer

Tentner

et al. 2022

Preprint

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Genotoxic stress in mammalian cells, including that caused by anti-cancer chemotherapy, can induce temporary cell cycle arrest, DNA damage-induced senescence (DDIS) or apoptotic cell death. Despite obvious clinical importance, it is unclear how the signals emerging from DNA damage are integrated together with other cellular signaling pathways monitoring the cell's environment and/or internal state to control these different cell fates. Here, using a combination of single cell-based signaling measurements and tensor PLSR/PCA computational approaches, we show that the JNK and Erk MAPK signaling pathways regulate the initiation of senescence through the transcription factor AP-1 at early times after extrinsic DNA damage, and the Senescence Associated Secretory Phenotype, a hallmark of DDIS, at late times after damage. These results identify a time-based separation of function for the same signaling pathways beyond the classic DNA damage response that control the cell senescence decision and modulate the tumor microenvironment following genotoxic stress, and reveal a fundamental similarity between signaling mechanisms responsible for oncogene-induced senescence and senescence caused by extrinsic DNA damaging agents.

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The heterogeneity of cellular senescence: insights at the single-cell level

Cited by 137 publications

References 45 publications

Shared enhancer gene regulatory networks between wound and oncogenic programs

Shared enhancer gene regulatory networks between wound and oncogenic programs

Generation of a transparent killifish line through multiplex CRISPR/Cas9-mediated gene inactivation

Biphasic JNK–Erk Signaling Separates Induction and Maintenance of Cell Senescence after DNA Damage

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