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.     

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.     

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.     

Role of polycomb group proteins in stem cell self-renewal and cancer

Polycomb group proteins (PcG) form part of a gene regulatory mechanism that determines cell fate during normal and pathogenic development. The mechanism relies on epigenetic modifications on specific histone tails that are inherited through cell divisions, thus behaving de facto as a cellular memory. This cellular memory governs key events in organismal development as well as contributing to the control of normal cell growth and differentiation. Consequently, the dysregulation of PcG genes, such as Bmi1, Pc2, Cbx7, and EZH2 has been linked with the aberrant proliferation of cancer cells. Furthermore, at least three PcG genes, Bmi1, Rae28, and Mel18, appear to regulate self-renewal of specific stem cell types suggesting a link between the maintenance of cellular homeostasis and tumorigenesis. In this review, we will briefly summarize current views on PcG function and the evidence linking specific PcG proteins with the behavior of stem cells and cancer cells.     

The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3

Polycomb group (PcG) proteins are important for maintaining the silenced state of homeotic genes. Biochemical and genetic studies in Drosophila and mammalian cells indicate that PcG proteins function in at least two distinct protein complexes: the ESC-E(Z) or EED-EZH2 complex, and the PRC1 complex. Recent work has shown that at least part of the silencing function of the ESC-E(Z) complex is mediated by its intrinsic activity for methylating histone H3 on lysine 27. In addition to being involved in Hox gene silencing, the complex and its associated histone methyltransferase activity are important in other biological processes including X-inactivation, germline development, stem cell pluripotency and cancer metastasis.     

Rm62, a DEAD‐box RNA helicase,complexes with DSP1 in Drosophila embryos

Two main classes of proteins, Polycomb group (PcG) and Trithorax group (TrxG), play a key role in the regulation of homeotic genes. These proteins act in multimeric complexes to remodel chromatin. A third class of proteins named Enhancers of Trithorax and Polycomb (ETP) modulates the activity of TrxG and PcG, but their role remains largely unknown. We previously identified an HMGB‐like protein, DSP1 (Dorsal Switch Protein 1), which was classified as an ETP. Preliminary studies have revealed that DSP1 is involved in multimeric complexes. Here we identify a DEAD‐box RNA helicase, Rm62, as partner of DSP1 in a 250‐kDa complex. Coimmunoprecipitation assays performed on embryo extracts indicate that DSP1 and Rm62 are associated in 3‐ to 12‐h embryos. Furthermore, DSP1 and Rm62 colocalize on polytene chromosomes. Consistent with these results, a mutation in Rm62 enhances a null mutation of dsp1 and also mutations of trxG or PcG, suggesting that Rm62 has characteristics of an ETP. We show here for the first time that an RNA helicase is involved in the maintenance of homeotic genes. genesis 48:244–253, 2010. © 2010 Wiley‐Liss, Inc.     

From flour to flower: how Polycomb group proteins influence multiple aspects of plant development

Cell identity and differentiation are determined by patterns of regulatory gene expression. Spatially and temporally regulated homeotic gene expression defines segment identities along the anterior-posterior axis of animal embryos. Polycomb group (PcG) proteins form a cellular memory system that maintains the repressed state of homeotic gene expression. Conserved PcG proteins control multiple aspects of Arabidopsis development and maintain homeotic gene repression. In animals, PcG proteins repress their target genes by modifying histone tails through deacetylation and methylation, generating a PcG-specific histone code that recruits other chromatin remodeling proteins to establish a stable, heritable mechanism of epigenetic expression control. Plant PcG proteins might function through a similar biochemical mechanism owing to their conserved structural and functional relationship to animal PcG proteins.     

Polycomb group and trithorax group proteins in Arabidopsis

Polycomb group (PcG) and trithorax group (trxG) proteins form molecular modules of a cellular memory mechanism that maintains gene expression states established by other regulators. In general, PcG proteins are responsible for maintaining a repressed expression state, whereas trxG proteins act in opposition to maintain an active expression state. This mechanism, first discovered in Drosophila and subsequently in mammals, has more recently been studied in plants. The characterization of several Polycomb Repressive Complex 2 (PRC2) components in Arabidopsis thaliana constituted a first breakthrough, revealing key roles of PcG proteins in the control of crucial plant developmental processes. Interestingly, the recent identification of plant homologues of the Drosophila trithorax protein suggests a conservation of both the PcG and trxG gene regulatory system in plants. Here, we review the current evidence for the role of PcG and trxG proteins in the control of plant development, their biochemical functions, their interplay in maintaining stable expression states of their target genes, and point out future directions which may help our understanding of PcG and trxG function in plants.