Increasing Notch signaling antagonizes PRC2-mediated silencing to promote reprograming of germ cells into neurons

Seelk, Stefanie; Adrian‐Kalchhauser, Irene; Hargitai, Balázs; Hajdůšková, Martina; Gutnik, Silvia; Tursun, Baris; Ciosk, Rafal

doi:10.7554/elife.15477

Cited by 35 publications

(60 citation statements)

References 72 publications

(100 reference statements)

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“…How is PRC2 recruited to the Notch ternary complex? Mechanisms for the recruitment of PRC2 to transcription factors remain elusive, but several models have been proposed (43–47). Jaird2 has been shown to link PRC2 to chromatin in ES cells (48).…”

Section: Discussionmentioning

confidence: 99%

Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

Han

Ranganathan

Tzimas

et al. 2017

Molecular Cancer Research

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It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb Repressor Complex 2 (PRC2) and Lysine Demethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape and repression of transcription. The demethylase activity of LSD1 is a pre-requisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex is identified containing LSD1, PRC2 and the Notch ternary complex. These findings demonstrate a novel function of Notch and provides further insight into the mechanisms of Notch-mediated tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

Han

Ranganathan

Tzimas

et al. 2017

Molecular Cancer Research

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“…Thus, while Notch is required for induction of Y cell fate, it is dispensable for the transition to neuronal cell fate. This Notch functionality may be analogous to the role of Notch signaling in germ cell conversion by antagonizing the repressive heterochromatin state established by PRC2 through expression of histone demethylases . Notch signaling may similarly establish a “memory state” in the Y cell which later permits the Y cell to lose its differentiated identity and gain plasticity (unipotential in this case).…”

Section: Commitment To Unipotency: Naturally Occurring Reprogrammingmentioning

confidence: 93%

“…Analysis of differential gene expression in GLP‐1/Notch loss‐of‐function and gain‐of‐function mutants suggests that Notch permits cell fate conversion by opposing PRC2 action. One identified focal point in this antagonistic relationship is UTX‐1, a JmjC domain‐containing H3K27me3 demethylase; PRC2 silences utx‐1 expression, while Notch signaling activates its expression . utx‐1 transcription is critical for Notch‐enhanced germ cell conversion, and therefore, UTX‐1 may be stimulated to promote reprogramming in the germ cell context.…”

Section: Totipotency To Commitment: Reprogramming In the Germlinementioning

confidence: 99%

The multipotency‐to‐commitment transition in Caenorhabditis elegans—implications for reprogramming from cells to organs

2018

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In animal embryos, cells transition from a multipotential state, with the capacity to adopt multiple fates, into an irreversible, committed state of differentiation. This multipotency-to-commitment transition (MCT) is evident from experiments in which cell fate is reprogrammed by transcription factors for cell type-specific differentiation, as has been observed extensively in Caenorhabditis elegans. Although factors that direct differentiation into each of the three germ layer types cannot generally reprogram cells after the MCT in this animal, transcription factors for endoderm development are able to do so in multiple differentiated cell types. In one case, these factors can redirect the development of an entire organ in the process of "transorganogenesis". Natural transdifferentiation also occurs in a small number of differentiated cells during normal C. elegans development. We review these reprogramming and transdifferentiation events, highlighting the cellular and developmental contexts in which they occur, and discuss common themes underlying direct cell lineage reprogramming. Although certain aspects may be unique to the model system, growing evidence suggests that some mechanisms are evolutionarily conserved and may shed light on cellular plasticity and disease in humans.

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“…In the adult germline, PRC2 buffers germ cells against reprogramming: forced expression of a master regulatory protein in the absence of PRC2 components leads to conversion of germ cells into somatic cell types (Patel et al, 2012). Increased GLP-1/Notch signaling in the germline antagonizes PRC2-mediated silencing of somatic genes to promote reprogramming (Seelk et al 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Expression profiling of germlines lacking P-granule components, PRC2 or MES-4 (Gaydos et al 2012;Knutson et al 2017;Campbell and Updike 2015), or undergoing forced reprogramming in the context of increased GLP-1/Notch signaling (Seelk et al 2016), has shown that loss of germ-cell identity is associated with expression of somatic genes. However, these approaches could not distinguish between genes whose misexpression causes versus is a consequence of a perturbed germline transcriptional program and sterility.…”

Section: Introductionmentioning

confidence: 99%

TheC. elegansSET-2 histone methyltransferase maintains germline fate by preventing progressive transcriptomic deregulation across generations

Robert

Knutson

Rechtsteiner

et al. 2019

Preprint

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Chromatin factors contribute to germline maintenance by preserving a germline-appropriate transcriptional program. In the absence of the conserved histone H3 Lys4 (H3K4) methyltransferase SET-2, C. elegans germ cells progressively lose their identity over generations, leading to sterility. How this transgenerational loss of fertility results from the absence of SET-2 is unknown. Here we performed expression profiling across generations on germlines from mutant animals lacking SET-2 activity. We found that gene deregulation occurred in 2 steps: a priming step in early generations progressing to loss of fertility in later generations. By performing Within-Class Analysis (WCA), a derivative of Principal Component Analysis, we identified transcriptional signatures associated with SET-2 inactivation, both at the priming step and later on during loss of fertility. Further analysis showed that repression of germline genes, derepression of somatic programs, and X-chromosome desilencing through interference with PRC2-dependent repression, are priming events driving loss of germline identity in the absence of SET-2. Decreasing expression of identified priming genes, including the C/EBP homologue cebp-1 and TGF- pathway components, was sufficient to delay the onset of sterility, suggesting that they individually contribute to the loss of germ cell fate. Altogether, our findings illustrate how the loss of a chromatin regulator at one generation can progressively deregulate multiple transcriptional and signaling programs, ultimately leading to loss of appropriate cell fate.

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Increasing Notch signaling antagonizes PRC2-mediated silencing to promote reprograming of germ cells into neurons

Cited by 35 publications

References 72 publications

Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex

The multipotency‐to‐commitment transition in Caenorhabditis elegans—implications for reprogramming from cells to organs

TheC. elegansSET-2 histone methyltransferase maintains germline fate by preventing progressive transcriptomic deregulation across generations

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