Mutations in the l(3)mbt tumour suppressor result in overproliferation of Drosophila larval brains. Recently, the derepression of different gene classes in l(3)mbt mutants was shown to be causal for transformation. However, the molecular mechanisms of dL(3)mbt-mediated gene repression are not understood. Here, we identify LINT, the major dL(3)mbt complex of Drosophila. LINT has three core subunits—dL(3)mbt, dCoREST, and dLint-1—and is expressed in cell lines, embryos, and larval brain. Using genome-wide ChIP–Seq analysis, we show that dLint-1 binds close to the TSS of tumour-relevant target genes. Depletion of the LINT core subunits results in derepression of these genes. By contrast, histone deacetylase, histone methylase, and histone demethylase activities are not required to maintain repression. Our results support a direct role of LINT in the repression of brain tumour-relevant target genes by restricting promoter access.
Vyšlo v časopise: LINT, a Novel dL(3)mbt-Containing Complex, Represses Malignant Brain Tumour Signature Genes. PLoS Genet 8(5): e32767. doi:10.1371/journal.pgen.1002676 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002676
1. BoniferCCockerillPN 2011 Chromatin mechanisms regulating gene expression in health and disease. Adv Exp Med Biol 711 12 25
2. GateffELofflerTWismarJ 1993 A temperature-sensitive brain tumor suppressor mutation of Drosophila melanogaster: developmental studies and molecular localization of the gene. Mech Dev 41 15 31
3. JanicAMendizabalLLlamazaresSRossellDGonzalezC 2011 Ectopic expression of germline genes drives malignant brain tumor growth in Drosophila. Science 330 1824 1827
4. RichterCOktabaKSteinmannJMullerJKnoblichJA 2011 The tumour suppressor L(3)mbt inhibits neuroepithelial proliferation and acts on insulator elements. Nat Cell Biol 13 1029 1039
5. TrojerPLiGSimsRJ3rdVaqueroAKalakondaN 2007 L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129 915 928
6. KalakondaNFischleWBoccuniPGurvichNHoya-AriasR 2008 Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1. Oncogene 27 4293 4304
7. LewisPWBeallELFleischerTCGeorletteDLinkAJ 2004 Identification of a Drosophila Myb-E2F2/RBF transcriptional repressor complex. Genes Dev 18 2929 2940
8. KorenjakMTaylor-HardingBBinneUKSatterleeJSStevauxO 2004 Native E2F/RBF complexes contain Myb-interacting proteins and repress transcription of developmentally controlled E2F target genes. Cell 119 181 193
9. DallmanJEAllopennaJBassettATraversAMandelG 2004 A conserved role but different partners for the transcriptional corepressor CoREST in fly and mammalian nervous system formation. J Neurosci 24 7186 7193
10. SchottaGSenguptaRKubicekSMalinSKauerM 2008 A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev 22 2048 2061
11. YangHPesaventoJJStarnesTWCrydermanDEWallrathLL 2008 Preferential dimethylation of histone H4 lysine 20 by Suv4-20. J Biol Chem 283 12085 12092
12. Di StefanoLJiJYMoonNSHerrADysonN 2007 Mutation of Drosophila Lsd1 disrupts H3-K4 methylation, resulting in tissue-specific defects during development. Curr Biol 17 808 812
13. Di StefanoLWalkerJABurgioGCoronaDFMulliganP 2011 Functional antagonism between histone H3K4 demethylases in vivo. Genes Dev 25 17 28
14. SimpsonAJCaballeroOLJungbluthAChenYTOldLJ 2005 Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5 615 625
15. MurawskaMKunertNvan VugtJLangstGKremmerE 2008 dCHD3, a novel ATP-dependent chromatin remodeler associated with sites of active transcription. Mol Cell Biol 28 2745 2757
16. KunertNWagnerEMurawskaMKlinkerHKremmerE 2009 dMec: a novel Mi-2 chromatin remodelling complex involved in transcriptional repression. Embo J 28 533 544
17. ScharfANMeierKSeitzVKremmerEBrehmA 2009 Monomethylation of lysine 20 on histone H4 facilitates chromatin maturation. Mol Cell Biol 29 57 67
18. MurawskaMHasslerMRenkawitz-PohlRLadurnerABrehmA 2011 Stress-induced PARP activation mediates recruitment of Drosophila Mi-2 to promote heat shock gene expression. PLoS Genet 7 e1002206 doi:10.1371/journal.pgen.1002206
19. LangmeadBTrapnellCPopMSalzbergSL 2009 Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10 R25
20. ZhangYLiuTMeyerCAEeckhouteJJohnsonDS 2008 Model-based analysis of ChIP-Seq (MACS). Genome Biol 9 R137
21. LeeMGWynderCCoochNShiekhattarR 2005 An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437 432 435
22. ShiYJMatsonCLanFIwaseSBabaT 2005 Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell 19 857 864
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