Transient loss of Polycomb components induces an epigenetic cancer fate
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ABSTRACT:
PROVIDER: PRJNA918577 | ENA |
REPOSITORIES: ENA
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Project description:Although cancer initiation and progression are generally associated with the accumulation of somatic mutations, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility, suggesting that genetic mechanisms might not be the only drivers of malignant transformation. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations is unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb Group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK-STAT signaling pathway and zfh1, the fly homolog of the ZEB1 oncogene, whose aberrant activation is required for Polycomb-induced tumorigenesis. These data show that a reversible perturbation of Polycomb Group protein levels can induce cancer in the absence of driver mutations, suggesting that tumors can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.
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Project description:Transient Polycomb activity represses developmental genes in growing oocytes.
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Project description:The Polycomb group (PcG) proteins form chromatin-modifying complexes that are essential for embryonic development and stem cell renewal and are commonly deregulated in cancer. Here, we identify their target genes using genome-wide location analysis in human embryonic fibroblasts. We find that Polycomb-Repressive Complex 1 (PRC1), PRC2, and tri-methylated histone H3K27 co-occupy >1000 silenced genes with a strong functional bias for embryonic development and cell fate decisions. We functionally identify 40 genes derepressed in human embryonic fibroblasts depleted of the PRC2 components (EZH2, EED, SUZ12) and the PRC1 component, BMI-1. Interestingly, several markers of osteogenesis, adipogenesis, and chrondrogenesis are among these genes, consistent with the mesenchymal origin of fibroblasts. Using a neuronal model of differentiation, we delineate two different mechanisms for regulating PcG target genes. For genes activated during differentiation, PcGs are displaced. However, for genes repressed during differentiation, we paradoxically find that they are already bound by the PcGs in nondifferentiated cells despite being actively transcribed. Our results are consistent with the hypothesis that PcGs are part of a preprogrammed memory system established during embryogenesis marking certain key genes for repressive signals during subsequent developmental and differentiation processes. Keywords: polycomb, development, differentiation, cell fate, stem cells, siRNA
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Project description:Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here, we apply multi-omics to comprehensively define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Integrating the chromatin-bound proteome and histone modification data sets reveals differences in the relative abundance and activities of distinct chromatin modules, identifying a strong enrichment of Polycomb Repressive Complex 2 (PRC2)-associated H3K27me3 in naive pluripotent stem cell chromatin. Single-cell approaches and human blastoid models reveal that PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, and inhibiting PRC2 promotes trophoblast fate induction and cavity formation. Our results establish that human naive pluripotent stem cells are not epigenetically unrestricted, but instead possess chromatin mechanisms that oppose the induction of alternative cell fates.
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Project description:Interactions between the genome and the nuclear pore complex (NPC) have been implicated in multiple gene regulatory processes, but the underlying logic of these interactions remains poorly defined. Here, we report high-resolution chromatin binding maps of two core components of the NPC, Nup107 and Nup93, which reveal differential binding of these NPC subunits to active genes and Polycomb-covered silent regions, respectively. Comparison to Lamin-associated domains (LADs) revealed that NPC binding sites are often found within LADs, demonstrating a linear binding of the genome along the nuclear envelope. Significantly, we identified a functional role of Nup93 in silencing of Polycomb target genes and in spatial folding of Polycomb domains. Our findings lend to a model where nuclear pores bind different types of chromatin via interactions with specific core sub-complexes of the NPC, and the Nup93 sub-complex functions as a stabilizing scaffold for Polycomb domains.
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Project description:Interactions between the genome and the nuclear pore complex (NPC) have been implicated in multiple gene regulatory processes, but the underlying logic of these interactions remains poorly defined. Here, we report high-resolution chromatin binding maps of two core components of the NPC, Nup107 and Nup93, which reveal differential binding of these NPC subunits to active genes and Polycomb-covered silent regions, respectively. Comparison to Lamin-associated domains (LADs) revealed that NPC binding sites are often found within LADs, demonstrating a linear binding of the genome along the nuclear envelope. Significantly, we identified a functional role of Nup93 in silencing of Polycomb target genes and in spatial folding of Polycomb domains. Our findings lend to a model where nuclear pores bind different types of chromatin via interactions with specific core sub-complexes of the NPC, and the Nup93 sub-complex functions as a stabilizing scaffold for Polycomb domains.
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Project description:Cell fate transitions involve rapid changes of gene expression patterns and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we used transcription-factor induced reprogramming of somatic cells into pluripotent cells to screen for novel regulators of cell fate change. We identified the RNA processing factor Nudt21, a component of the pre-mRNA cleavage and polyadenylation complex, as a potent barrier to reprogramming. Importantly, suppression of Nudt21 not only enhanced the generation of induced pluripotent stem cells but also facilitated the conversion of fibroblasts into trophoblast stem cells and delayed the differentiation of myeloid precursor cells into macrophages, suggesting a broader role for Nudt21 in restricting cell fate change. Polyadenylation site sequencing (PAS-seq) revealed that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency. While only a fraction of these transcripts changed expression at the protein level, this fraction was strongly enriched for chromatin regulators, including components of the PAF, polycomb, and trithorax complexes. Co-suppression analysis further suggests that these chromatin factors are largely responsible for Nudt21’s effect on reprogramming, providing a mechanistic basis for our observations. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of mammalian cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling.
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Project description:The Gcm/Glide transcription factor is transiently expressed and required in the Drosophila nervous system. Threshold Gcm/Glide levels control the glial versus neuronal fate choice, and its perdurance triggers excessive gliogenesis, showing that its tight and dynamic regulation ensures the proper balance between neurons and glia. Here, we present a genetic screen for potential gcm/glide interactors and identify genes encoding chromatin factors of the Trithorax and of the Polycomb groups. These proteins maintain the heritable epigenetic state, among others, of HOX genes throughout development, but their regulatory role on transiently expressed genes remains elusive. Here we show that Polycomb negatively affects Gcm/Glide autoregulation, a positive feedback loop that allows timely accumulation of Gcm/Glide threshold levels. Such temporal fine-tuning of gene expression tightly controls gliogenesis. This work performed at the levels of individual cells reveals an undescribed mode of Polycomb action in the modulation of transiently expressed fate determinants and hence in the acquisition of specific cell identity in the nervous system.
| S-EPMC3531469 | biostudies-literature