title: Coordinated regulation of Myc trans-activation targets by Polycomb and the Trithorax group protein Ash1.
abstract: BACKGROUND
  The Myc oncoprotein is a transcriptional regulator whose function is essential for normal development. Myc is capable of binding to 10% of the mammalian genome, and it is unclear how a developing embryo controls the DNA binding of its abundant Myc proteins in order to avoid Myc's potential for inducing tumorigenesis.
  
  
  RESULTS
  To identify chromatin binding proteins with a potential role in controlling Myc activity, we established a genetic assay for dMyc activity in Drosophila. We conducted a genome-wide screen using this assay, and identified the Trithorax Group protein Ash1 as a modifier of dMyc activity. Ash1 is a histone methyltransferase known for its role in opposing repression by Polycomb. Using RNAi in the embryo and Affymetrix microarrays, we show that ash1 RNAi causes the increased expression of many genes, suggesting that it is directly or indirectly required for repression in the embryo, in contrast to its known role in maintenance of activation. Many of these genes also respond similarly upon depletion of Pc and pho transcripts, as determined by concurrent microarray analysis of Pc and pho RNAi embryos, suggesting that the three are required for low levels of expression of a common set of targets. Further, many of these overlapping targets are also activated by Myc overexpression. We identify a second group of genes whose expression in the embryo requires Ash1, consistent with its previously established role in maintenance of activation. We find that this second group of Ash1 targets overlaps those activated by Myc and that ectopic Myc overcomes their requirement for Ash1.
  
  
  CONCLUSIONS
  Genetic, genomic and chromatin immunoprecipitation data suggest a model in which Pc, Ash1 and Pho are required to maintain a low level of expression of embryonic targets of activation by Myc, and that this occurs, directly or indirectly, by a combination of disparate chromatin modifications.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. jmgoodli@uncc.edu
authors.forename: Julie M
authors.initials: JM
authors.lastname: Goodliffe
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cole
authors.forename: Eric
authors.initials: E
authors.lastname: Wieschaus
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C490910:ASH1 protein, Drosophila; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C066770:Pc protein, Drosophila; D063146:Polycomb-Group Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C113295:pho protein, Drosophila; C071050:Psc protein, Drosophila; D063150:Polycomb Repressive Complex 1