Coordinated regulation of Myc trans-activation targets by Polycomb and the Trithorax group protein Ash1
Tóm tắt
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. 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. 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.
Tài liệu tham khảo
Cole MD, McMahon SB: The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation. Oncogene. 1999, 18 (19): 2916-2924. 10.1038/sj.onc.1202748
Patel JH, Loboda AP, Showe MK, Showe LC, McMahon SB: Analysis of genomic targets reveals complex functions of MYC. Nat Rev Cancer. 2004, 4 (7): 562-568. 10.1038/nrc1393
Pelengaris S, Khan M, Evan G: c-MYC: more than just a matter of life and death. Nat Rev Cancer. 2002, 2 (10): 764-776. 10.1038/nrc904
Adhikary S, Eilers M: Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol. 2005, 6 (8): 635-645. 10.1038/nrm1703
Mao DY, Barsyte-Lovejoy D, Ho CS, Watson JD, Stojanova A, Penn LZ: Promoter-binding and repression of PDGFRB by c-Myc are separable activities. Nucleic Acids Res. 2004, 32 (11): 3462-3468. 10.1093/nar/gkh669
Guccione E, Martinato F, Finocchiaro G, Luzi L, Tizzoni L, Dall' Olio V, Zardo G, Nervi C, Bernard L, Amati B: Myc-binding-site recognition in the human genome is determined by chromatin context. Nat Cell Biol. 2006, 8 (7): 764-770. 10.1038/ncb1434
Gallant P, Shiio Y, Cheng PF, Parkhurst SM, Eisenman RN: Myc and Max homologs in Drosophila. Science. 1996, 274 (5292): 1523-1527. 10.1126/science.274.5292.1523
Schreiber-Agus N, Stein D, Chen K, Goltz JS, Stevens L, DePinho RA: Drosophila Myc is oncogenic in mammalian cells and plays a role in the diminutive phenotype. Proc Natl Acad Sci U S A. 1997, 94 (4): 1235-1240. 10.1073/pnas.94.4.1235
Trumpp A, Refaeli Y, Oskarsson T, Gasser S, Murphy M, Martin GR, Bishop JM: c-Myc regulates mammalian body size by controlling cell number but not cell size. Nature. 2001, 414 (6865): 768-773. 10.1038/414768a
de la Cova C, Abril M, Bellosta P, Gallant P, Johnston LA: Drosophila myc regulates organ size by inducing cell competition. Cell. 2004, 117 (1): 107-116. 10.1016/S0092-8674(04)00214-4
Grewal SS, Li L, Orian A, Eisenman RN, Edgar BA: Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nat Cell Biol. 2005, 7 (3): 295-302. 10.1038/ncb1223
Maines JZ, Stevens LM, Tong X, Stein D: Drosophila dMyc is required for ovary cell growth and endoreplication. Development. 2004, 131 (4): 775-786. 10.1242/dev.00932
Moreno E, Basler K: dMyc transforms cells into super-competitors. Cell. 2004, 117 (1): 117-129. 10.1016/S0092-8674(04)00262-4
Pierce SB, Yost C, Britton JS, Loo LW, Flynn EM, Edgar BA, Eisenman RN: dMyc is required for larval growth and endoreplication in Drosophila. Development. 2004, 131 (10): 2317-2327. 10.1242/dev.01108
Beer S, Zetterberg A, Ihrie RA, McTaggart RA, Yang Q, Bradon N, Arvanitis C, Attardi LD, Feng S, Ruebner B, Cardiff RD, Felsher DW: Developmental context determines latency of MYC-induced tumorigenesis. PLoS Biol. 2004, 2 (11): e332- 10.1371/journal.pbio.0020332
Levine SS, King IF, Kingston RE: Division of labor in polycomb group repression. Trends Biochem Sci. 2004, 29 (9): 478-485. 10.1016/j.tibs.2004.07.007
Ringrose L, Paro R: Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet. 2004, 38: 413-443. 10.1146/annurev.genet.38.072902.091907
Goodliffe JM, Wieschaus E, Cole MD: Polycomb mediates Myc autorepression and its transcriptional control of many loci in Drosophila. Genes Dev. 2005, 19 (24): 2941-2946. 10.1101/gad.1352305
Campbell RB, Sinclair DA, Couling M, Brock HW: Genetic interactions and dosage effects of Polycomb group genes of Drosophila. Mol Gen Genet. 1995, 246 (3): 291-300. 10.1007/BF00288601
Simon J, Chiang A, Bender W: Ten different Polycomb group genes are required for spatial control of the abdA and AbdB homeotic products. Development. 1992, 114 (2): 493-505.
Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R: Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006, 441 (7091): 349-353. 10.1038/nature04733
Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K: Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006, 20 (9): 1123-1136. 10.1101/gad.381706
Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP, Melton DA, Gifford DK, Jaenisch R, Young RA: Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006, 125 (2): 301-313. 10.1016/j.cell.2006.02.043
Negre N, Hennetin J, Sun LV, Lavrov S, Bellis M, White KP, Cavalli G: Chromosomal Distribution of PcG Proteins during Drosophila Development. PLoS Biol. 2006, 4 (6): e170- 10.1371/journal.pbio.0040170
Tolhuis B, de Wit E, Muijrers I, Teunissen H, Talhout W, van Steensel B, van Lohuizen M: Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nat Genet. 2006, 38 (6): 694-699. 10.1038/ng1792
Muller J, Kassis JA: Polycomb response elements and targeting of Polycomb group proteins in Drosophila. Curr Opin Genet Dev. 2006, 16 (5): 476-484. 10.1016/j.gde.2006.08.005
Pirrotta V, Poux S, Melfi R, Pilyugin M: Assembly of Polycomb complexes and silencing mechanisms. Genetica. 2003, 117 (2-3): 191-197. 10.1023/A:1022992011833
Brown JL, Mucci D, Whiteley M, Dirksen ML, Kassis JA: The Drosophila Polycomb group gene pleiohomeotic encodes a DNA binding protein with homology to the transcription factor YY1. Mol Cell. 1998, 1 (7): 1057-1064. 10.1016/S1097-2765(00)80106-9
Klymenko T, Papp B, Fischle W, Kocher T, Schelder M, Fritsch C, Wild B, Wilm M, Muller J: A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities. Genes Dev. 2006, 20 (9): 1110-1122. 10.1101/gad.377406
Mohd-Sarip A, Cleard F, Mishra RK, Karch F, Verrijzer CP: Synergistic recognition of an epigenetic DNA element by Pleiohomeotic and a Polycomb core complex. Genes Dev. 2005, 19 (15): 1755-1760. 10.1101/gad.347005
Mohd-Sarip A, Venturini F, Chalkley GE, Verrijzer CP: Pleiohomeotic can link polycomb to DNA and mediate transcriptional repression. Mol Cell Biol. 2002, 22 (21): 7473-7483. 10.1128/MCB.22.21.7473-7483.2002
Wang L, Brown JL, Cao R, Zhang Y, Kassis JA, Jones RS: Hierarchical recruitment of polycomb group silencing complexes. Mol Cell. 2004, 14 (5): 637-646. 10.1016/j.molcel.2004.05.009
Brock HW, Fisher CL: Maintenance of gene expression patterns. Dev Dyn. 2005, 232 (3): 633-655. 10.1002/dvdy.20298
Francis NJ, Saurin AJ, Shao Z, Kingston RE: Reconstitution of a functional core polycomb repressive complex. Mol Cell. 2001, 8 (3): 545-556. 10.1016/S1097-2765(01)00316-1
Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y: Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002, 298 (5595): 1039-1043. 10.1126/science.1076997
Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V: Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 2002, 111 (2): 185-196. 10.1016/S0092-8674(02)00975-3
Muller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B, Miller EL, O'Connor MB, Kingston RE, Simon JA: Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell. 2002, 111 (2): 197-208. 10.1016/S0092-8674(02)00976-5
Bellen HJ, Levis RW, Liao G, He Y, Carlson JW, Tsang G, Evans-Holm M, Hiesinger PR, Schulze KL, Rubin GM, Hoskins RA, Spradling AC: The BDGP gene disruption project: single transposon insertions associated with 40% of Drosophila genes. Genetics. 2004, 167 (2): 761-781. 10.1534/genetics.104.026427
Lukacsovich T, Asztalos Z, Awano W, Baba K, Kondo S, Niwa S, Yamamoto D: Dual-tagging gene trap of novel genes in Drosophila melanogaster. Genetics. 2001, 157 (2): 727-742.
Schwartz YB, Kahn TG, Nix DA, Li XY, Bourgon R, Biggin M, Pirrotta V: Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nat Genet. 2006, 38 (6): 700-705. 10.1038/ng1817
Chekmenev DS, Haid C, Kel AE: P-Match: transcription factor binding site search by combining patterns and weight matrices. Nucleic Acids Res. 2005, 33 (Web Server issue): W432-7. 10.1093/nar/gki441
Hulf T, Bellosta P, Furrer M, Steiger D, Svensson D, Barbour A, Gallant P: Whole-genome analysis reveals a strong positional bias of conserved dMyc-dependent E-boxes. Mol Cell Biol. 2005, 25 (9): 3401-3410. 10.1128/MCB.25.9.3401-3410.2005
Orian A, van Steensel B, Delrow J, Bussemaker HJ, Li L, Sawado T, Williams E, Loo LW, Cowley SM, Yost C, Pierce S, Edgar BA, Parkhurst SM, Eisenman RN: Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes Dev. 2003, 17 (9): 1101-1114. 10.1101/gad.1066903
Srinivasan L, Atchison ML: YY1 DNA binding and PcG recruitment requires CtBP. Genes Dev. 2004, 18 (21): 2596-2601. 10.1101/gad.1228204
Beisel C, Imhof A, Greene J, Kremmer E, Sauer F: Histone methylation by the Drosophila epigenetic transcriptional regulator Ash1. Nature. 2002, 419 (6909): 857-862. 10.1038/nature01126
Byrd KN, Shearn A: ASH1, a Drosophila trithorax group protein, is required for methylation of lysine 4 residues on histone H3. Proc Natl Acad Sci U S A. 2003, 100 (20): 11535-11540. 10.1073/pnas.1933593100
Klymenko T, Muller J: The histone methyltransferases Trithorax and Ash1 prevent transcriptional silencing by Polycomb group proteins. EMBO Rep. 2004, 5 (4): 373-377. 10.1038/sj.embor.7400111
LaJeunesse D, Shearn A: Trans-regulation of thoracic homeotic selector genes of the Antennapedia and bithorax complexes by the trithorax group genes: absent, small, and homeotic discs 1 and 2. Mech Dev. 1995, 53 (1): 123-139. 10.1016/0925-4773(95)00430-0
Shearn A: The ash-1, ash-2 and trithorax genes of Drosophila melanogaster are functionally related. Genetics. 1989, 121 (3): 517-525.
Tripoulas N, LaJeunesse D, Gildea J, Shearn A: The Drosophila ash1 gene product, which is localized at specific sites on polytene chromosomes, contains a SET domain and a PHD finger. Genetics. 1996, 143 (2): 913-928.
Tripoulas NA, Hersperger E, La Jeunesse D, Shearn A: Molecular genetic analysis of the Drosophila melanogaster gene absent, small or homeotic discs1 (ash1). Genetics. 1994, 137 (4): 1027-1038.
Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES: A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006, 125 (2): 315-326. 10.1016/j.cell.2006.02.041
Gildea JJ, Lopez R, Shearn A: A screen for new trithorax group genes identified little imaginal discs, the Drosophila melanogaster homologue of human retinoblastoma binding protein 2. Genetics. 2000, 156 (2): 645-663.
Shearn A, Rice T, Garen A, Gehring W: Imaginal disc abnormalities in lethal mutants of Drosophila. Proc Natl Acad Sci U S A. 1971, 68 (10): 2594-2598. 10.1073/pnas.68.10.2594
Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T: Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 2001, 410 (6824): 120-124. 10.1038/35065138
Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T: Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001, 410 (6824): 116-120. 10.1038/35065132
Nakayama J, Rice JC, Strahl BD, Allis CD, Grewal SI: Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science. 2001, 292 (5514): 110-113. 10.1126/science.1060118
Gehring WJ: A recessive lethal [l(4)29] with a homeotic effect in D. melanogaster. Drosophila Information Services. 1970, 45: 103-
Girton JR, Jeon SH: Novel embryonic and adult homeotic phenotypes are produced by pleiohomeotic mutations in Drosophila. Dev Biol. 1994, 161 (2): 393-407. 10.1006/dbio.1994.1040
Poux S, McCabe D, Pirrotta V: Recruitment of components of Polycomb Group chromatin complexes in Drosophila. Development. 2001, 128 (1): 75-85.
Mishra RK, Mihaly J, Barges S, Spierer A, Karch F, Hagstrom K, Schweinsberg SE, Schedl P: The iab-7 polycomb response element maps to a nucleosome-free region of chromatin and requires both GAGA and pleiohomeotic for silencing activity. Mol Cell Biol. 2001, 21 (4): 1311-1318. 10.1128/MCB.21.4.1311-1318.2001
Busturia A, Lloyd A, Bejarano F, Zavortink M, Xin H, Sakonju S: The MCP silencer of the Drosophila Abd-B gene requires both Pleiohomeotic and GAGA factor for the maintenance of repression. Development. 2001, 128 (11): 2163-2173.
Brown JL, Fritsch C, Mueller J, Kassis JA: The Drosophila pho-like gene encodes a YY1-related DNA binding protein that is redundant with pleiohomeotic in homeotic gene silencing. Development. 2003, 130 (2): 285-294. 10.1242/dev.00204
Johnston LA, Prober DA, Edgar BA, Eisenman RN, Gallant P: Drosophila myc regulates cellular growth during development. Cell. 1999, 98 (6): 779-790. 10.1016/S0092-8674(00)81512-3
Sanson B, White P, Vincent JP: Uncoupling cadherin-based adhesion from wingless signalling in Drosophila. Nature. 1996, 383 (6601): 627-630. 10.1038/383627a0
Kennerdell JR, Carthew RW: Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the wingless pathway. Cell. 1998, 95 (7): 1017-1026. 10.1016/S0092-8674(00)81725-0