RESUMO
Histone H3 Lysine 9 (H3K9) methylation, a characteristic mark of heterochromatin, is progressively implemented during development to contribute to cell fate restriction as differentiation proceeds. Accordingly, in undifferentiated and pluripotent mouse Embryonic Stem (ES) cells the global levels of H3K9 methylation are rather low and increase only upon differentiation. How global H3K9 methylation levels are coupled with the loss of pluripotency remains largely unknown. Here, we identify SUV39H1, a major H3K9 di- and tri-methylase, as an indirect target of the pluripotency network of Transcription Factors (TFs). We find that pluripotency TFs, principally OCT4, activate the expression of Suv39h1as, an antisense long non-coding RNA to Suv39h1. In turn, Suv39h1as downregulates Suv39h1 transcription in cis via a mechanism involving the modulation of the chromatin status of the locus. The targeted deletion of the Suv39h1as promoter region triggers increased SUV39H1 expression and H3K9me2 and H3K9me3 levels, affecting all heterochromatic regions, particularly peri-centromeric major satellites and retrotransposons. This increase in heterochromatinization efficiency leads to accelerated and more efficient commitment into differentiation. We report, therefore, a simple genetic circuitry coupling the genetic control of pluripotency with the global efficiency of H3K9 methylation associated with a major cell fate restriction, the irreversible loss of pluripotency.
Assuntos
Histonas , Metiltransferases/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , RNA Longo não Codificante , Proteínas Repressoras/metabolismo , Animais , Cromatina , Código das Histonas , Histonas/genética , Histonas/metabolismo , Metilação , Metiltransferases/genética , Camundongos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/genéticaRESUMO
Mitotic bookmarking transcription factors (BFs) maintain the capacity to bind to their targets during mitosis, despite major rearrangements of the chromatin. While they were thought to propagate gene regulatory information through mitosis by statically occupying their DNA targets, it has recently become clear that BFs are highly dynamic in mitotic cells. This represents both a technical and a conceptual challenge to study and understand the function of BFs: First, formaldehyde has been suggested to be unable to efficiently capture these transient interactions, leading to profound contradictions in the literature; and second, if BFs are not permanently bound to their targets during mitosis, it becomes unclear how they convey regulatory information to daughter cells. Here, comparing formaldehyde to alternative fixatives we clarify the nature of the chromosomal association of previously proposed BFs in embryonic stem cells: While ESRRB can be considered as a canonical BF that binds at selected regulatory regions in mitosis, SOX2 and POU5F1 (also known as OCT4) establish DNA sequence-independent interactions with the mitotic chromosomes, either throughout the chromosomal arms (SOX2) or at pericentromeric regions (POU5F1). Moreover, we show that ordered nucleosomal arrays are retained during mitosis at ESRRB bookmarked sites, whereas regions losing transcription factor binding display a profound loss of order. By maintaining nucleosome positioning during mitosis, ESRRB might ensure the rapid post-mitotic re-establishment of functional regulatory complexes at selected enhancers and promoters. Our results provide a mechanistic framework that reconciles dynamic mitotic binding with the transmission of gene regulatory information across cell division.
Assuntos
Mitose/genética , Nucleossomos/química , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , Cromatina/metabolismo , Cromossomos de Mamíferos , Fixadores , Formaldeído , Camundongos , Receptores de Estrogênio/metabolismo , SuccinimidasRESUMO
Polycomb group (PcG) proteins dynamically define cellular identities through epigenetic repression of key developmental genes. PcG target gene repression can be stabilized through the interaction in the nucleus at PcG foci. Here, we report the results of a high-resolution microscopy genome-wide RNAi screen that identifies 129 genes that regulate the nuclear organization of Pc foci. Candidate genes include PcG components and chromatin factors, as well as many protein-modifying enzymes, including components of the SUMOylation pathway. In the absence of SUMO, Pc foci coagulate into larger aggregates. Conversely, loss of function of the SUMO peptidase Velo disperses Pc foci. Moreover, SUMO and Velo colocalize with PcG proteins at PREs, and Pc SUMOylation affects its chromatin targeting, suggesting that the dynamic regulation of Pc SUMOylation regulates PcG-mediated silencing by modulating the kinetics of Pc binding to chromatin as well as its ability to form Polycomb foci.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Cromatina/metabolismo , Análise por Conglomerados , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Técnicas de Silenciamento de Genes , Ontologia Genética , Discos Imaginais/citologia , Discos Imaginais/metabolismo , Fenótipo , Ligação Proteica , Transporte Proteico , Interferência de RNA , SumoilaçãoRESUMO
The changes imposed on the nucleus, chromatin and its regulators during mitosis lead to the dismantlement of most gene regulatory processes. However, an increasing number of transcriptional regulators are being identified as capable of binding their genomic targets during mitosis. These so-called 'mitotic bookmarking factors' encompass transcription factors and chromatin modifiers that are believed to convey gene regulatory information from mother to daughter cells. In this Primer, we review mitotic bookmarking processes in development and stem cells and discuss the interest and potential importance of this concept with regard to epigenetic regulation and cell fate transitions involving cellular proliferation.
Assuntos
Mitose , Células-Tronco/citologia , Animais , Ciclo Celular , Diferenciação Celular , Linhagem da Célula , Núcleo Celular/metabolismo , Cromatina/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA , Proteínas de Drosophila , Neurogênese/genética , Complexo Repressor Polycomb 1 , Fatores de Transcrição , Animais , Diferenciação Celular , Linhagem da Célula/genética , Cromatina/genética , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of SRY is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer is required for appropriate SRY expression to initiate testis-determination in humans. Comparative sequence analysis of SRY 5' regions in mammals identified an evolutionary conserved SF-1/NR5A1-binding motif within a 250 bp region of open chromatin located 5 kilobases upstream of the SRY transcription start site. Genomic analysis of 46,XY individuals with disrupted testis-determination, including a large multigenerational family, identified unique single-base substitutions of highly conserved residues within the SF-1/NR5A1-binding element. In silico modelling and in vitro assays demonstrate the enhancer properties of the NR5A1 motif. Deletion of this hemizygous element by genome-editing, in a novel in vitro cellular model recapitulating human Sertoli cell formation, resulted in a significant reduction in expression of SRY. Therefore, human NR5A1 acts as a regulatory switch between testis and ovary development by upregulating SRY expression, a role that may predate the eutherian radiation. We show that disruption of an enhancer can phenocopy variants in the coding regions of SRY that cause human testis dysgenesis. Since disease causing variants in enhancers are currently rare, the regulation of gene expression in testis-determination offers a paradigm to define enhancer activity in a key developmental process.
Assuntos
Disgenesia Gonadal , Testículo , Animais , Feminino , Humanos , Masculino , Linhagem Celular , Mamíferos/genética , Sequências Reguladoras de Ácido Nucleico , Células de Sertoli/metabolismo , Proteína da Região Y Determinante do Sexo/genética , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo , Testículo/metabolismoRESUMO
When cells enter mitosis, they undergo series of dramatic changes in their structure and function that severely hamper gene regulatory processes and gene transcription. This raises the question of how daughter cells efficiently recapitulate the gene expression profile of their mother such that cell identity can be preserved. Here, we review recent evidence supporting the view that distinct chromatin-associated mechanisms of gene-regulatory inheritance assist daughter cells in the postmitotic reestablishment of gene activity with increased fidelity.
Assuntos
Mitose , Cromatina , Cromossomos , Regulação da Expressão Gênica , HumanosRESUMO
Broccoli is a source of bioactive compounds that provide an important nutritional value. The content of these compounds can vary depending on agronomic and environmental conditions, as well as on elicitation. In this study, three crop trials were carried out to evaluate the effects of the cultivation season, the application of different dosages of methyl-jasmonate (MeJA) on the overall quality and on the total content of bioactive compounds of 'Parthenon' broccoli cultivated under the field conditions of southeastern Spain. Color parameters, chlorophyll content, total phenolic compounds, total flavonoids and antioxidant activity were measured to evaluate the overall quality. Moreover, individual carotenoids, phenolic compounds and glucosinolates were evaluated by high performance liquid chromatography with diode array detection (HPLC-DAD) and high performance liquid chromatography equipped with diode array detector coupled to mass spectrometer using electro spray ionization (HPLC-DAD-ESI/MSn). The content of total carotenoids, phenolic compounds and glucosinolates were higher in autumn compared with spring, showing increases of 2.8-fold, 2-fold and 1.2-fold, respectively. Moreover, a double application of MeJA increased the contents of total carotenoids, phenolic compounds and glucosinolates by 22%, 32% and 39%, respectively, relative to the untreated samples. Considering our results, the controlled and timely application of 250 µM MeJA to the aerial parts of the plants four days before harvest, on two consecutive days, seems to be a valid agronomic strategy to improve the health-promoting capacity of Parthenon broccoli, without compromising its overall quality.
RESUMO
The Drosophila dRYBP gene has been described to function as a Polycomb-dependent transcriptional repressor. To determine the in vivo function of the dRYBP gene, we have generated mutations and analyzed the associated phenotypes. Homozygous null mutants die progressively throughout development and present phenotypes variable both in their penetrance and in their expressivity, including disrupted oogenesis, a disorganized pattern of the syncytial nuclear divisions, defects in pattern formation, and decreased wing size. Although dRYBP mutations do not show the homeotic-like phenotypes typical of mutations in the PcG and trxG genes, they enhance the phenotypes of mutations of either the Sex comb extra gene (PcG) or the trithorax gene (trxG). Finally, the dRYBP protein interacts physically with the Sex comb extra and the Pleiohomeotic proteins, and the homeotic-like phenotypes produced by the high levels of the dRYBP protein are mediated through its C-terminal domain. Our results indicate that the dRYBP gene functions in the control of cell identity together with the PcG/trxG proteins. Furthermore, they also indicate that dRYBP participates in the control of cell proliferation and cell differentiation and we propose that its functional requirement may well depend on the robustness of the animal.
Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Genes de Insetos , Proteínas Repressoras/genética , Animais , Núcleo Celular/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Embrião não Mamífero/citologia , Regulação da Expressão Gênica no Desenvolvimento , Larva/crescimento & desenvolvimento , Masculino , Mutação/genética , Especificidade de Órgãos , Fenótipo , Estrutura Terciária de Proteína , Transporte Proteico , Interferência de RNA , Proteínas Repressoras/química , Proteínas Repressoras/metabolismoRESUMO
Transcription factor networks, together with histone modifications and signalling pathways, underlie the establishment and maintenance of gene regulatory architectures associated with the molecular identity of each cell type. However, how master transcription factors individually impact the epigenomic landscape and orchestrate the behaviour of regulatory networks under different environmental constraints is only partially understood. Here, we show that the transcription factor Nanog deploys multiple distinct mechanisms to enhance embryonic stem cell self-renewal. In the presence of LIF, which fosters self-renewal, Nanog rewires the pluripotency network by promoting chromatin accessibility and binding of other pluripotency factors to thousands of enhancers. In the absence of LIF, Nanog blocks differentiation by sustaining H3K27me3, a repressive histone mark, at developmental regulators. Among those, we show that the repression of Otx2 plays a preponderant role. Our results underscore the versatility of master transcription factors, such as Nanog, to globally influence gene regulation during developmental processes.
Assuntos
Autorrenovação Celular/fisiologia , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Proteína Homeobox Nanog/metabolismo , Animais , Linhagem Celular , Autorrenovação Celular/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Código das Histonas/genética , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , Camundongos , Proteína Homeobox Nanog/genética , Fatores de Transcrição Otx/genética , Fatores de Transcrição Otx/metabolismoRESUMO
The access of Transcription Factors (TFs) to their cognate DNA binding motifs requires a precise control over nucleosome positioning. This is especially important following DNA replication and during mitosis, both resulting in profound changes in nucleosome organization over TF binding regions. Using mouse Embryonic Stem (ES) cells, we show that the TF CTCF displaces nucleosomes from its binding site and locally organizes large and phased nucleosomal arrays, not only in interphase steady-state but also immediately after replication and during mitosis. Correlative analyses suggest this is associated with fast gene reactivation following replication and mitosis. While regions bound by other TFs (Oct4/Sox2), display major rearrangement, the post-replication and mitotic nucleosome positioning activity of CTCF is not unique: Esrrb binding regions are also characterized by persistent nucleosome positioning. Therefore, selected TFs such as CTCF and Esrrb act as resilient TFs governing the inheritance of nucleosome positioning at regulatory regions throughout the cell-cycle.
Assuntos
Fator de Ligação a CCCTC/metabolismo , Replicação do DNA , Células-Tronco Embrionárias/fisiologia , Mitose , Nucleossomos/metabolismo , Animais , Células Cultivadas , Regulação da Expressão Gênica , Camundongos , Ativação TranscricionalRESUMO
The propagation and maintenance of gene expression programs are at the foundation of the preservation of cell identity. A large and complex set of epigenetic mechanisms enables the long-term stability and inheritance of transcription states. A key property of authentic epigenetic regulation is being independent from the instructive signals used for its establishment. This makes epigenetic regulation, particularly epigenetic silencing, extremely robust and powerful to lock regulatory states and stabilise cell identity. In line with this, the establishment of epigenetic silencing during development restricts cell potency and maintains the cell fate choices made by transcription factors (TFs). However, how more immature cells that have not yet established their definitive fate maintain their transitory identity without compromising their responsiveness to signalling cues remains unclear. A paradigmatic example is provided by pluripotent embryonic stem (ES) cells derived from a transient population of cells of the blastocyst. Here, we argue that ES cells represent an interesting "epigenetic paradox": even though they are captured in a self-renewing state characterised by extremely efficient maintenance of their identity, which is a typical manifestation of robust epigenetic regulation, they seem not to heavily rely on classical epigenetic mechanisms. Indeed, self-renewal strictly depends on the TFs that previously instructed their undifferentiated identity and relies on a particular signalling-dependent chromatin state where repressive chromatin marks play minor roles. Although this "epigenetic paradox" may underlie their exquisite responsiveness to developmental cues, it suggests that alternative mechanisms to faithfully propagate gene regulatory states might be prevalent in ES cells.
Assuntos
Células-Tronco Embrionárias/fisiologia , Epigênese Genética , Células-Tronco Pluripotentes/fisiologia , Animais , Diferenciação Celular , Cromatina/metabolismo , Expressão Gênica , Humanos , Camundongos , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
At the kilo- to megabase pair scales, eukaryotic genomes are partitioned into self-interacting modules or topologically associated domains (TADs) that associate to form nuclear compartments. Here, we combine high-content super-resolution microscopies with state-of-the-art DNA-labeling methods to reveal the variability in the multiscale organization of the Drosophila genome. We find that association frequencies within TADs and between TAD borders are below ~10%, independently of TAD size, epigenetic state, or cell type. Critically, despite this large heterogeneity, we are able to visualize nanometer-sized epigenetic domains at the single-cell level. In addition, absolute contact frequencies within and between TADs are to a large extent defined by genomic distance, higher-order chromosome architecture, and epigenetic identity. We propose that TADs and compartments are organized by multiple, small-frequency, yet specific interactions that are regulated by epigenetics and transcriptional state.
Assuntos
Cromossomos/genética , Drosophila/genética , Animais , Cromatina/genética , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Cromossomos/química , Cromossomos/metabolismo , Drosophila/química , Drosophila/metabolismo , Epigênese Genética , Genoma , Análise de Célula ÚnicaRESUMO
The Polycomb and trithorax groups of genes control the maintenance of homeotic gene expression in a variety of organisms. A putative participant in the regulation of this process is the murine RYBP (Ring and YY1 Binding Protein) gene. Sequence comparison between different species has identified the homologous gene in Drosophila, the dRYBP gene. We have investigated whether dRYBP participates in the mechanisms of silencing of homeotic genes expression. We first studied its expression by RNA in situ hybridisation and detected dRYBP expression ubiquitously and throughout development. Moreover, we generated a polyclonal anti-dRYBP antibody that recognises the dRYBP protein. dRYBP protein is nuclear and expressed maternally and ubiquitously throughout development. To study the transcriptional activity of dRYBP, we generated a fusion protein containing the entire dRYBP protein and the GAL4 DNA binding domain. This fusion protein functions, in vivo, as a transcriptional repressor throughout development. Importantly, this repression is dependent on the function of the Polycomb group genes. Furthermore, using the GAL4/UAS system, we have over expressed dRYBP in the haltere and the wing imaginal discs. In the haltere discs, high levels of dRYBP repress the expression of the homeotic Ultrabithorax gene. This repression is Polycomb dependent. In the wing discs, dRYBP over expression produces a variety of phenotypes suggesting the overall miss regulation of the many putative genes affected by high levels of dRYBP. Taking together, our results indicate that dRYBP is able to interact with PcG proteins to repress transcription suggesting that the dRYBP gene might belong to the Polycomb group of genes in Drosophila.
Assuntos
Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila/genética , Regulação da Expressão Gênica , Proteínas Repressoras/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Dados de Sequência Molecular , Mutação , Complexo Repressor Polycomb 1 , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Ativação TranscricionalRESUMO
Alternative pre-mRNA splicing is a highly cell type-specific process essential to generating protein diversity. However, the mechanisms responsible for the establishment and maintenance of heritable cell-specific alternative-splicing programs are poorly understood. Recent observations point to a role of histone modifications in the regulation of alternative splicing. Here we report a new mechanism of chromatin-mediated splicing control involving a long noncoding RNA (lncRNA). We have identified an evolutionarily conserved nuclear antisense lncRNA, generated from within the human FGFR2 locus, that promotes epithelial-specific alternative splicing of FGFR2. The lncRNA acts through recruitment of Polycomb-group proteins and the histone demethylase KDM2a to create a chromatin environment that impairs binding of a repressive chromatin-splicing adaptor complex important for mesenchymal-specific splicing. Our results uncover a new function for lncRNAs in the establishment and maintenance of cell-specific alternative splicing via modulation of chromatin signatures.
Assuntos
Processamento Alternativo/genética , Cromatina/genética , Precursores de RNA/genética , RNA Longo não Codificante/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Proteínas Argonautas/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular , RNA Helicases DEAD-box/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Células Epiteliais , Fatores de Iniciação em Eucariotos/genética , Proteínas F-Box/metabolismo , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Células MCF-7 , Proteínas de Neoplasias , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Interferência de RNA , RNA Interferente Pequeno , Ribonuclease III/genética , Fatores de TranscriçãoRESUMO
Drosophila RYBP (dRYBP; Ring1 and YY1 Binding Protein) is a Polycomb and trithorax interacting protein, whose homologous RYBP/DEDAF mammalian counterparts exhibit tumor cell-specific killing activity. Here we show that although endogenous dRYBP is not involved in developmental apoptosis, high levels of exogenous dRYBP induce apoptosis in all the imaginal discs of the fly, indicating that dRYBP apoptotic activity is not specific to tumor cells. We also show that dRYBP-induced apoptosis is inhibited by high levels of either p35 or DIAP1 (Drosophila Inhibitor of Apoptosis Protein 1), and requires the function of the pro-apoptotic REAPER, HID and GRIM proteins, the apical caspase DREDD, the adaptor dFADD protein as well as TRITHORAX (TRX), an epigenetic transcriptional regulator. Furthermore, we demonstrate that overexpression of TRX also induces apoptosis in the imaginal discs. Finally, we show that the expression of reaper-lacZ is upregulated both upon dRYBP-induced apoptosis and upon TRX-induced apoptosis in imaginal discs and that the reaper gene is a direct target of dRYBP in Drosophila embryos. Our results indicate that dRYBP triggers in a receptor-mediated apoptotic pathway that also includes TRX-dependent epigenetic regulation of gene expression.
Assuntos
Apoptose , Caspases/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Proteínas Repressoras/metabolismo , Animais , Proteínas de Drosophila/genética , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Regiões Promotoras GenéticasRESUMO
Epigenetic mechanisms controlling cellular proliferation are essential to animal development. Moreover, altered levels of expression of the epigenetic regulator proteins are associated with the development and progression of human diseases like cancer. We have studied the effects of high levels of Polyhomeotic (PH) protein, a member of the Polycomb Group (PcG), during the proliferation of the imaginal discs in Drosophila. Overexpression of PH protein causes induction of proliferation, accompanied with induction of JNK-dependent apoptosis. As a result, massive hyperplastic overgrowth is produced and the corresponding differentiated tissues show phenotypes related with mis-regulation of homeotic gene expression. We have found that high levels of PH upregulate the JAK/STAT pathway through the de-repression of Unpaired (UPD), the extracellular ligand of the Drosophila JAK/STAT signalling cascade. Moreover, inactivation of the JAK/STAT pathway in the presence of a large amount of PH protein greatly reduces the tissue overgrowth, demonstrating a functional role of JAK/STAT in PH-induced hyperplasia. Finally, we have observed that decapentaplegic and d-myc, two growth genes and putative targets of the JAK/STAT pathway, are also overexpressed in the PH-induced tumors. We propose that during normal development, the PcG proteins act to maintain inactive the JAK/STAT pathway. Upon cellular stress, changes in the levels of PcG proteins expression are induced and JAK/STAT is activated leading to tumor development. Our results show a functional relationship between the PcG gene expression and the JAK/STAT pathway, both of which are found to be perturbed in tumorigenesis.