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SUZ12, a component of the PRC2 complex, can also function as a tumour suppressor in certain tumours of the nervous system and melanomas. Interaction of PRC2 with Ras pathway The PRC2 complex, which regulates gene expression through chromatin modification, has been shown to play a pro-tumorigenic role in many tumours. Karen Cichowski and colleagues now show that SUZ12, a component of PRC2, can also function as a tumour suppressor in certain tumours of the nervous system and melanomas. Through deregulation of chromatin and thereby gene expression, SUZ12 loss cooperates with the loss of NF1, another tumour suppressor frequently lost in these tumours types. At the same time, SUZ12 loss renders tumours sensitive to drugs that target bromodomain proteins, which are currently being explored for a number of cancer types. This work reveals an unexpected connection between PRC2 and several components of the Ras pathway, as well as providing possible targets for epigenetic-based therapies. The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types 1 . However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer 2 , 3 . Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1 . NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras 4 . We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.

Polycomb repressive complex 2 (PRC2) is a key mammalian epigenetic regulator that supports neuron specification during development. In this paper, the authors find that PRC2 plays a role in the survival of adult neurons. The loss of PRC2 activity in adult striatum led to the de-repression of multiple genes with bivalent histone methylation marks and to a fatal neurodegeneration phenotype. Normal brain function depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. Neuronal specification is driven by transcriptional programs that are established during early neuronal development and remain in place in the adult brain. The fidelity of neuronal specification depends on the robustness of the transcriptional program that supports the neuron type-specific gene expression patterns. Here we show that polycomb repressive complex 2 (PRC2), which supports neuron specification during differentiation, contributes to the suppression of a transcriptional program that is detrimental to adult neuron function and survival. We show that PRC2 deficiency in striatal neurons leads to the de-repression of selected, predominantly bivalent PRC2 target genes that are dominated by self-regulating transcription factors normally suppressed in these neurons. The transcriptional changes in PRC2-deficient neurons lead to progressive and fatal neurodegeneration in mice. Our results point to a key role of PRC2 in protecting neurons against degeneration.

The production of haematopoietic stem cells is repressed during early mammalian embryogenesis by an epigenetic mechanism that involves the action of the Polycomb protein EZH1. EZH1 controls multipotency of blood stem cells The first blood-cell progenitors that arise in mammalian embryos are lineage-restricted. Multipotent haematopoietic stem cells, which can differentiate into any type of blood cell, emerge only later during gestation. George Daley and colleagues show that this second-stage haematopoietic program, which is at the origin of all adult blood cells, is repressed during early embryogenesis through an epigenetic mechanism involving the action of the polycomb protein EZH1. Reducing EZH1 expression in human pluripotent stem cells in vitro unleashes their capacity to develop into multiple lymphoid lineages. In mouse embryos, reduced EZH1 expression promotes the precocious emergence of definitive haematopoietic stem cells. All haematopoietic cell lineages that circulate in the blood of adult mammals derive from multipotent haematopoietic stem cells (HSCs) 1 . By contrast, in the blood of mammalian embryos, lineage-restricted progenitors arise first, independently of HSCs, which only emerge later in gestation 2 , 3 . As best defined in the mouse, ‘primitive’ progenitors first appear in the yolk sac at 7.5 days post-coitum 2 , 3 . Subsequently, erythroid–myeloid progenitors that express fetal haemoglobin 4 , as well as fetal lymphoid progenitors 5 , develop in the yolk sac and the embryo proper, but these cells lack HSC potential. Ultimately, ‘definitive’ HSCs with long-term, multilineage potential and the ability to engraft irradiated adults emerge at 10.5 days post-coitum from arterial endothelium in the aorta-gonad-mesonephros and other haemogenic vasculature 3 . The molecular mechanisms of this reverse progression of haematopoietic ontogeny remain unexplained. We hypothesized that the definitive haematopoietic program might be actively repressed in early embryogenesis through epigenetic silencing 6 , and that alleviating this repression would elicit multipotency in otherwise lineage-restricted haematopoietic progenitors. Here we show that reduced expression of the Polycomb group protein EZH1 enhances multi-lymphoid output from human pluripotent stem cells. In addition, Ezh1 deficiency in mouse embryos results in precocious emergence of functional definitive HSCs in vivo . Thus, we identify EZH1 as a repressor of haematopoietic multipotency in the early mammalian embryo.

Protection against deadly pathogens requires the production of high-affinity antibodies by B cells, which are generated in germinal centers (GCs). Alteration of the GC developmental program is common in many B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions, including lymphomas. The histone H3 lysine 27 methyltransferase enhancer of zeste homolog 2 (EZH2) is highly expressed in GC B cells and is often constitutively activated in GC-derived non-Hodgkin lymphomas (NHLs). The function of EZH2 in GC B cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells caused profound impairment of GC responses, memory B cell formation, and humoral immunity. EZH2 protected GC B cells against activation-induced cytidine deaminase (AID) mutagenesis, facilitated cell cycle progression, and silenced plasma cell determinant and tumor suppressor B-lymphocyte-induced maturation protein 1 (BLIMP1). EZH2 inhibition in NHL cells induced BLIMP1, which impaired tumor growth. In conclusion, EZH2 sustains AID function and prevents terminal differentiation of GC B cells, which allows antibody diversification and affinity maturation. Dysregulation of the GC reaction by constitutively active EZH2 facilitates lymphomagenesis and identifies EZH2 as a possible therapeutic target in NHL and other GC-derived B cell diseases.

Loss-of-function mutations of EZH2 , a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2 . Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2 -null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9 . These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners. Mutations in the EZH2 gene are found in myelodysplastic syndrome (MDS) and are often accompanied by mutations in RUNX1 . Here, the authors develop a mouse model of MDS and show that EZH2 loss enhances the RUNX1-mediated MDS pathology.

While the Polycomb complex is known to regulate cell identity in ES cells, its role in controlling tissue‐specific stem cells is not well understood. Here we show that removal of Ezh1 and Ezh2, key Polycomb subunits, from mouse skin results in a marked change in fate determination in epidermal progenitor cells, leading to an increase in the number of lineage‐committed Merkel cells, a specialized subtype of skin cells involved in mechanotransduction. By dissecting the genetic mechanism, we showed that the Polycomb complex restricts differentiation of epidermal progenitor cells by repressing the transcription factor Sox2. Ablation of Sox2 results in a dramatic loss of Merkel cells, indicating that Sox2 is a critical regulator of Merkel cell specification. We show that Sox2 directly activates Atoh1 , the obligate regulator of Merkel cell differentiation. Concordantly, ablation of Sox2 attenuated the Ezh1/2 ‐null phenotype, confirming the importance of Polycomb‐mediated repression of Sox2 in maintaining the epidermal progenitor cell state. Together, these findings define a novel regulatory network by which the Polycomb complex maintains the progenitor cell state and governs differentiation in vivo . Ezh1/2‐mediated repression of the transcription factor Sox2 in epidermal progenitors extends the role of Polycomb proteins in controlling cellular identity beyond ES cells towards tissue‐specific stem cells.

Imprinted X-inactivation silences genes exclusively on the paternally-inherited X-chromosome and is a paradigm of transgenerational epigenetic inheritance in mammals. Here, we test the role of maternal vs. zygotic Polycomb repressive complex 2 (PRC2) protein EED in orchestrating imprinted X-inactivation in mouse embryos. In maternal-null (Eedm-/-) but not zygotic-null (Eed-/-) early embryos, the maternal X-chromosome ectopically induced Xist and underwent inactivation. Eedm-/- females subsequently stochastically silenced Xist from one of the two X-chromosomes and displayed random X-inactivation. This effect was exacerbated in embryos lacking both maternal and zygotic EED (Eedmz-/-), suggesting that zygotic EED can also contribute to the onset of imprinted X-inactivation. Xist expression dynamics in Eedm-/- embryos resemble that of early human embryos, which lack oocyte-derived maternal PRC2 and only undergo random X-inactivation. Thus, expression of PRC2 in the oocyte and transmission of the gene products to the embryo may dictate the occurrence of imprinted X-inactivation in mammals. Almost every one of our cells, with a few exceptions, contains the complete set of genes needed to build and maintain the human body. Yet, not all of these genes are active in every cell. Instead, some genes are tagged for activation, while others are silenced. These changes do not alter the genetic code, only how it is read by the cell, and are collectively referred to as epigenetics. Female mammals have two X-chromosomes compared to males' one. As such, females will silence one of those chromosomes to avoid getting a double-dose from those genes located on the X-chromosome. This epigenetic process is called X-chromosome inactivation, and it lasts for the life of the animal. Epigenetic information can also be passed on to future generations. In early female embryos of mice, for example, it is always the X-chromosome inherited from the father that is suppressed, which suggests that the instructions for which X-chromosome to inactivate must have come from the parents. Harris, Cloutier et al. set out to dissect the mechanics of the specialised form of X-chromosome inactivation seen in female embryos of mice, which is known as imprinted X-inactivation. A protein called EED was suspected to play a key role. Embryos inherit EED protein from the mother's egg, so it was reasoned that this protein may be the epigenetic link between the generations. The cascade of epigenetic events leading to imprinted X-inactivation in the early embryo has been well-defined, but the role of maternal EED was yet to be tested. The experiments showed that the mother's EED protein was needed to silence the father's X-chromosome in female mouse embryos. Without EED from the mother's egg, early embryos failed to initiate imprinted X-inactivation and reverted instead to random X-inactivation, where either X-chromosome is chosen for silencing in female cells. This pattern resembles what happens in early human embryos, which are unable to undergo imprinted X-inactivation because a woman's eggs lack the EED protein. Together these new findings trace the passage of epigenetic information from parent to offspring at the molecular level. With evidence like this, scientists can better understand mechanisms of non-genetic inheritance more broadly, including from parent to offspring.

Objective The Polycomb Repressive Complex 2 (PRC2) regulates neural stem cell behaviour during development of the cerebral cortex, yet how the loss of PRC2 developmentally influences cell identity in the mature brain is poorly defined. Using a mouse model in which the PRC2 gene Embryonic ectoderm development ( Eed) was conditionally deleted from the developing mouse dorsal telencephalon, we performed single nuclei RNA sequencing (snRNA-seq) on the cortical plate of an adult heterozygote Eed knockout mouse and an adult homozygote Eed knockout mouse compared to a littermate control. This work was part of a larger effort to understand consequences of mutations to PRC2 within the mature brain. Results Here we provide snRNA-seq data from the cortical plate of an adult heterozygous conditional Eed knockout, an adult homozygous conditional Eed knockout and an adult control mouse. This data provides insight on how loss of PRC2 function during development affects cell identity in the mature cortex.

Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non‐small‐cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3‐deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co‐treatment with 3‐deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co‐treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co‐treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co‐treatment strongly suppressed EGFR signaling, not only in EGFR‐wild‐type NSCLC cells, but also in EGFR‐mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co‐treatment suppressed the in vivo tumor growth of EGFR‐mutant, EGFR–tyrosine kinase‐resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC. The present study clearly demonstrated that the combined therapy with inhibitors of the histone methylase EZH2 and the histone de acetylases HDACs had a synergistic growth suppressive effect and induced substantial apoptosis in NSCLC cells. Interestingly, the co‐treatment suppressed the in vivo tumor growth of EGFR‐mutant, EGFR‐TKI‐resistant H1975 cells more effectively than single treatment via inhibition of the EGFR signaling pathway, suggesting that the combined pharmacological targeting of the histone modification enzymes may provide more effective epigenetic therapeutics for NSCLC including that with EGFR‐TKI‐resistant mutations.

Trimethylation on H3K27 mediated by Polycomb Repressive Complex 2 (PRC2) is required to control gene repression programs involved in development, regulation of tissue homeostasis or maintenance and lineage specification of stem cells. In Drosophila , the PRC2 catalytic subunit is the single protein E(z), while in mammals this function is fulfilled by two proteins, Ezh1 and Ezh2. Based on database searches, we propose that Ezh1 arose from an Ezh2 gene duplication that has occurred in the common ancestor to elasmobranchs and bony vertebrates. Expression studies in zebrafish using in situ hybridization and RT-PCR followed by the sequencing of the amplicon revealed that ezh1 mRNAs are maternally deposited. Then, ezh1 transcripts are ubiquitously distributed in the entire embryo at 24 hpf and become more restricted to anterior part of the embryo at later developmental stages. To unveil the function of ezh1 in zebrafish, a mutant line was generated using the TALEN technology. Ezh1-deficient mutant fish are viable and fertile, but the loss of ezh1 function is responsible for the earlier death of ezh2 mutant larvae indicating that ezh1 contributes to zebrafish development in absence of zygotic ezh2 gene function. Furthermore, we show that presence of ezh1 transcripts from the maternal origin accounts for the delayed lethality of ezh2 -deficient larvae.