The enhancer of trithorax and polycomb corto interacts with cyclin G in Drosophila

Background

Polycomb (PcG) and trithorax (trxG) genes encode proteins involved in the maintenance of gene expression patterns, notably Hox genes, throughout development. PcG proteins are required for long-term gene repression whereas TrxG proteins are positive regulators that counteract PcG action. PcG and TrxG proteins form large complexes that bind chromatin at overlapping sites called Polycomb and Trithorax Response Elements (PRE/TRE). A third class of proteins, so-called “Enhancers of Trithorax and Polycomb” (ETP), interacts with either complexes, behaving sometimes as repressors and sometimes as activators. The role of ETP proteins is largely unknown.

Methodology/Principal Findings

In a two-hybrid screen, we identified Cyclin G (CycG) as a partner of the Drosophila ETP Corto. Inactivation of CycG by RNA interference highlights its essential role during development. We show here that Corto and CycG directly interact and bind to each other in embryos and S2 cells. Moreover, CycG is targeted to polytene chromosomes where it co-localizes at multiple sites with Corto and with the PcG factor Polyhomeotic (PH). We observed that corto is involved in maintaining Abd-B repression outside its normal expression domain in embryos. This could be achieved by association between Corto and CycG since both proteins bind the regulatory element iab-7 PRE and the promoter of the Abd-B gene.

Conclusions/Significance

Our results suggest that CycG could regulate the activity of Corto at chromatin and thus be involved in changing Corto from an Enhancer of TrxG into an Enhancer of PcG.     

Extra sex combs, chromatin, and cancer: exploring epigenetic regulation and tumorigenesis in Drosophila

Developmental genetic studies in Drosophila unraveled the importance of Polycomb group (PcG) and Trithorax group (TrxG) genes in controlling cellular identity.PcG and TrxG proteins form histone modifying complexes that catalyze repressive or activating histone modifications,respectively,and thus maintaining the expression status of homeotic genes.Human orthologs of PcG and TrxG genes are implicated in tumorigenesis as well as in determining the prognosis of individual cancers.Recent whole genome analyses of cancers also highlighted the importance of histone modifying proteins in controlling tumorigenesis.Comprehensive understanding of the mechanistic relationship between histone regulation and tumorigenesis holds the promise of significantly advancing our understanding and management of cancer.It is anticipated that Drosophila melanogaster,the model organism that contributed significantly to our understanding of the functional role of histone regulation in development,could also provide unique insight for our understanding of how histone dysregulation can lead to cancer.In this review,we will discuss several recent advances in this regard.     

Quantitative in vivo analysis of chromatin binding of Polycomb and Trithorax group proteins reveals retention of ASH1 on mitotic chromatin

The Polycomb (PcG) and Trithorax (TrxG) group proteins work antagonistically on several hundred developmentally important target genes, giving stable mitotic memory, but also allowing flexibility of gene expression states. How this is achieved in quantitative terms is poorly understood. Here, we present a quantitative kinetic analysis in living Drosophila of the PcG proteins Enhancer of Zeste, (E(Z)), Pleiohomeotic (PHO) and Polycomb (PC) and the TrxG protein absent, small or homeotic discs 1 (ASH1). Fluorescence recovery after photobleaching and fluorescence correlation spectroscopy reveal highly dynamic chromatin binding behaviour for all proteins, with exchange occurring within seconds. We show that although the PcG proteins substantially dissociate from mitotic chromatin, ASH1 remains robustly associated with chromatin throughout mitosis. Finally, we show that chromatin binding by ASH1 and PC switches from an antagonistic relationship in interphase, to a cooperative one during mitosis. These results provide quantitative insights into PcG and TrxG chromatin-binding dynamics and have implications for our understanding of the molecular nature of epigenetic memory.     

Extra sex combs, chromatin, and cancer: Exploring epigenetic regulation and tumorigenesis in Drosophila

Developmental genetic studies in Drosophila unraveled the importance of Polycomb group (PcG) and Trithorax group (TrxG) genes in controlling cellular identity.PcG and TrxG proteins form histone modifying complexes that catalyze repressive or activating histone modifications,respectively,and thus maintaining the expression status of homeotic genes.Human orthologs of PcG and TrxG genes are implicated in tumorigenesis as well as in determining the prognosis of individual cancers.Recent whole genome analyses of cancers also highlighted the importance of histone modifying proteins in controlling tumorigenesis.Comprehensive understanding of the mechanistic relationship between histone regulation and tumorigenesis holds the promise of significantly advancing our understanding and management of cancer.It is anticipated that Drosophila melanogaster,the model organism that contributed significantly to our understanding of the functional role of histone regulation in development,could also provide unique insight for our understanding of how histone dysregulation can lead to cancer.In this review,we will discuss several recent advances in this regard.     

Polycomb and trithorax control genome expression by determining the alternative epigenetic states of chromatin for key developmental regulators

The Polycomb (PcG) and Trithorax (TrxG) group proteins are essential for development in all multicellular organisms. Mutations of the PcG and TrxG genes act as early embryonic lethals, while their overexpression correlates with malignancies. Comparative genome analysis showed that PcG and TrxG form a binary regulatory system that functions as an epigenetic rheostat to determine the threshold levels of extracellular signals affecting the expression levels of key developmental genes.     

Polycomb and Trithorax control genome expression by determining the alternative chromatin epigenetic states for key developmental regulators

The Polycomb (PcG) and Trithorax (TrxG) group proteins are essential for development in all multicellular organisms. Mutations of the PcG and TrxG genes act as early embryonic lethals, while their overexpression correlates with malignancies. Comparative genomic analysis showed that PcG and TrxG form a binary regulatory system that functions as an epigenetic rheostat to determine the threshold levels of extracellular signals affecting the expression levels of key developmental genes.     

The Arabidopsis homologs of trithorax (ATX1) and enhancer of zeste (CLF) establish 'bivalent chromatin marks' at the silent AGAMOUS locus

Tightly balanced antagonism between the Polycomb group (PcG) and the Trithorax group (TrxG) complexes maintain Hox expression patterns in Drosophila and murine model systems. Factors belonging to the PcG/TrxG complexes control various processes in plants as well but whether they participate in mechanisms that antagonize, balance or maintain each other's effects at a particular gene locus is unknown. CURLY LEAF (CLF), an Arabidopsis homolog of enhancer of zeste (EZ) and the ARABIDOPSIS HOMOLOG OF TRITHORAX (ATX1) control the expression of the flower homeotic gene AGAMOUS (AG). Disrupted ATX1 or CLF function results in misexpression of AG, recognizable phenotypes and loss of H3K4me3 or H3K27me3 histone H3-tail marks, respectively. A novel idea suggested by our results here, is that PcG and TrxG complexes function as a specific pair generating bivalent chromatin marks at the silent AG locus. Simultaneous loss of ATX1 and CLF restored AG repression and normalized leaf phenotypes. At the molecular level, disrupted ATX1 and CLF functions did not lead to erasure of the CLF- and ATX1-generated epigenetic marks, as expected: instead, in the double mutants, H3K27me3 and H3K4me3 tags were partially restored. We demonstrate that ATX1 and CLF physically interact linking mechanistically the observed effects.     

Maintenance of the patterns of expression of homeotic genes in the development of <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> by proteins of the polycomb,trithorax, and ETP groups

Proteins encoded by genes of the Polycomb (PcG), trithorax (trxG), and the Enhancer of trithorax and Polycomb (ETP) groups are important regulators of expression of most developmental genes. Data concerning all currently described genes assigned to these groups are summarized in the review. Genetic interactions of these genes and phenotypic manifestation of their mutations are described. Data on the PcG, trxG, and ETP proteins are systematized. Questions are considered concerning the formation of multimeric complexes containing proteins of these groups, recruitment of these complexes to regulatory elements of target genes, and the mechanisms of activation/repression of gene expression.     

Diverse functions of Polycomb group proteins during plant development

Polycomb group (PcG) proteins play essential roles in animal and plant life cycles by controlling the expression of important developmental regulators. These structurally heterogeneous proteins form multimeric protein complexes that control higher order chromatin structure and, thereby, the expression state of their target genes. Once established, PcG proteins maintain silent gene expression states over many cell divisions providing a molecular basis for a cellular 'memory.' PcG proteins are best known for their role in the control of homeotic genes in Drosophila and mammals. In addition, they play important roles in the control of cell proliferation in vertebrate and invertebrate systems. Recent studies in plants have shown that PcG proteins regulate diverse developmental processes and, as in animals, they affect both homeotic gene expression and cell proliferation. Thus, the function of PcG proteins has been widely conserved between the plant and animal kingdoms.