Autoregulation of the Noncoding RNA Gene
Most genes along the male single X chromosome in Drosophila are hypertranscribed about two-fold relative to each of the two female X chromosomes. This is accomplished by the MSL (male-specific lethal) complex that acetylates histone H4 at lysine 16. The MSL complex contains two large noncoding RNAs, roX1 (RNA on X) and roX2, that help target chromatin modifying enzymes to the X. The roX RNAs are functionally redundant but differ in size, sequence, and transcriptional control. We wanted to find out how roX1 production is regulated. Ectopic DC can be induced in wild-type (roX1+ roX2+) females if we provide a heterologous source of MSL2. However, in the absence of roX2, we found that roX1 expression failed to come on reliably. Using an in situ hybridization probe that is specific only to endogenous roX1, we found that expression was restored if we introduced either roX2 or a truncated but functional version of roX1. This shows that pre-existing roX RNA is required to positively autoregulate roX1 expression. We also observed massive cis spreading of the MSL complex from the site of roX1 transcription at its endogenous location on the X chromosome. We propose that retention of newly assembled MSL complex around the roX gene is needed to drive sustained transcription and that spreading into flanking chromatin contributes to the X chromosome targeting specificity. Finally, we found that the gene encoding the key male-limited protein subunit, msl2, is transcribed predominantly during DNA replication. This suggests that new MSL complex is made as the chromatin template doubles. We offer a model describing how the production of roX1 and msl2, two key components of the MSL complex, are coordinated to meet the dosage compensation demands of the male cell.
Vyšlo v časopise:
Autoregulation of the Noncoding RNA Gene. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002564
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002564
Souhrn
Most genes along the male single X chromosome in Drosophila are hypertranscribed about two-fold relative to each of the two female X chromosomes. This is accomplished by the MSL (male-specific lethal) complex that acetylates histone H4 at lysine 16. The MSL complex contains two large noncoding RNAs, roX1 (RNA on X) and roX2, that help target chromatin modifying enzymes to the X. The roX RNAs are functionally redundant but differ in size, sequence, and transcriptional control. We wanted to find out how roX1 production is regulated. Ectopic DC can be induced in wild-type (roX1+ roX2+) females if we provide a heterologous source of MSL2. However, in the absence of roX2, we found that roX1 expression failed to come on reliably. Using an in situ hybridization probe that is specific only to endogenous roX1, we found that expression was restored if we introduced either roX2 or a truncated but functional version of roX1. This shows that pre-existing roX RNA is required to positively autoregulate roX1 expression. We also observed massive cis spreading of the MSL complex from the site of roX1 transcription at its endogenous location on the X chromosome. We propose that retention of newly assembled MSL complex around the roX gene is needed to drive sustained transcription and that spreading into flanking chromatin contributes to the X chromosome targeting specificity. Finally, we found that the gene encoding the key male-limited protein subunit, msl2, is transcribed predominantly during DNA replication. This suggests that new MSL complex is made as the chromatin template doubles. We offer a model describing how the production of roX1 and msl2, two key components of the MSL complex, are coordinated to meet the dosage compensation demands of the male cell.
Zdroje
1. KhalilAMGuttmanMHuarteMGarberMRajA 2009 Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A 106 11667 11672
2. OromUADerrienTBeringerMGumireddyKGardiniA 2010 Long noncoding RNAs with enhancer-like function in human cells. Cell 143 46 58
3. DengXMellerVH 2006 Non-coding RNA in fly dosage compensation. Trends Biochem Sci 31 526 532
4. GelbartMKurodaM 2009 Drosophila dosage compensation: a complex voyage to the X chromosome. Development 136 1399 1410
5. HilfikerAHilfiker-KleinerDPannutiALucchesiJC 1997 mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J 16 2054 2060
6. AkhtarABeckerPB 2000 Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol Cell 5 367 375
7. BoneJRLavenderJRichmanRPalmerMJTurnerBM 1994 Acetylated histone H4 on the male X chromosome is associated with dosage compensation in Drosophila. Genes Dev 8 96 104
8. SmithERAllisCDLucchesiJC 2001 Linking global histone acetylation to the transcription enhancement of X-chromosomal genes in Drosophila males. J Biol Chem 276 31483 31486
9. WuLZeeBMWangYGarciaBADouY 2011 The RING Finger Protein MSL2 in the MOF Complex Is an E3 Ubiquitin Ligase for H2B K34 and Is Involved in Crosstalk with H3 K4 and K79 Methylation. Mol Cell 43 132 144
10. AmreinHAxelR 1997 Genes expressed in neurons of adult male Drosophila. Cell 88 459 469
11. MellerVHGordadzePRParkYChuXStuckenholzC 2000 Ordered assembly of roX RNAs into MSL complexes on the dosage-compensated X chromosome in Drosophila. Curr Biol 10 136 143
12. FrankeABakerBS 1999 The roX1 and roX2 RNAs are essential components of the compensasome, which mediates dosage compensation in Drosophila. Mol Cell 4 117 122
13. KelleyRLLeeOKShimYK 2008 Transcription rate of noncoding roX1 RNA controls local spreading of the Drosophila MSL chromatin remodeling complex. Mech Dev 125 1009 1019
14. ParkSWKangYSypulaJGChoiJOhH 2007 An evolutionarily conserved domain of roX2 RNA is sufficient for induction of H4-Lys16 acetylation on the Drosophila X chromosome. Genetics 177 1429 1437
15. MellerVHWuKHRomanGKurodaMIDavisRL 1997 roX1 RNA paints the X chromosome of male Drosophila and is regulated by the dosage compensation system. Cell 88 445 457
16. MellerVH 2003 Initiation of dosage compensation in Drosophila embryos depends on expression of the roX RNAs. Mech Dev 120 759 767
17. MellerVHRattnerBP 2002 The roX genes encode redundant male-specific lethal transcripts required for targeting of the MSL complex. EMBO J 21 1084 1091
18. ParkYKelleyRLOhHKurodaMIMellerVH 2002 Extent of chromatin spreading determined by roX RNA recruitment of MSL proteins. Science 298 1620 1623
19. OhHParkYKurodaMI 2003 Local spreading of MSL complexes from roX genes on the Drosophila X chromosome. Genes Dev 17 1334 1339
20. BashawGJBakerBS 1997 The regulation of the Drosophila msl-2 gene reveals a function for Sex-lethal in translational control. Cell 89 789 798
21. KelleyRLWangJBellLKurodaMI 1997 Sex lethal controls dosage compensation in Drosophila by a non-splicing mechanism. Nature 387 195 199
22. FauthTMuller-PlanitzFKonigCStraubTBeckerPB 2010 The DNA binding CXC domain of MSL2 is required for faithful targeting the Dosage Compensation Complex to the X chromosome. Nucleic Acids Res 38 3209 3221
23. BhadraUPal-BhadraMBirchlerJA 1999 Role of the male specific lethal (msl) genes in modifying the effects of sex chromosomal dosage in Drosophila. Genetics 152 249 268
24. BhadraUPal-BhadraMBirchlerJA 2000 Histone acetylation and gene expression analysis of Sex lethal mutants in Drosophila. Genetics 155 753 763
25. DahlsveenIKGilfillanGDShelestVILammRBeckerP 2006 Targeting Determinants of Dosage Compensation in Drosophila. PLoS Genet 2 e5 doi:10.1371/journal.pgen.0020005
26. GilfillanGDKonigCDahlsveenIKPrakouraNStraubT 2007 Cumulative contributions of weak DNA determinants to targeting the Drosophila dosage compensation complex. Nucleic Acids Res 35 3561 3572
27. GuWSzauterPLucchesiJC 1998 Targeting of MOF, a putative histone acetyl transferase, to the X chromosome of Drosophila melanogaster. Dev Genet 22 56 64
28. KindJAkhtarA 2007 Cotranscriptional recruitment of the dosage compensation complex to X-linked target genes. Genes Dev 21 2030 2040
29. LymanLMCoppsKRastelliLKelleyRLKurodaMI 1997 Drosophila male-specific lethal-2 protein: structure/function analysis and dependence on MSL-1 for chromosome association. Genetics 147 1743 1753
30. KelleyRLSolovyevaILymanLMRichmanRSolovyevV 1995 Expression of msl-2 causes assembly of dosage compensation regulators on the X chromosomes and female lethality in Drosophila. Cell 81 867 877
31. LiFSchiemannAHScottMJ 2008 Incorporation of the noncoding roX RNAs alters the chromatin-binding specificity of the Drosophila MSL1/MSL2 complex. Mol Cell Biol 28 1252 1264
32. RattnerBPMellerVH 2004 Drosophila male-specific lethal 2 protein controls sex-specific expression of the roX genes. Genetics 166 1825 1832
33. BaiXAlekseyenkoAAKurodaMI 2004 Sequence-specific targeting of MSL complex regulates transcription of the roX RNA genes. EMBO J 23 2853 2861
34. FrankeADernburgABashawGJBakerBS 1996 Evidence that MSL-mediated dosage compensation in Drosophila begins at blastoderm. Development 122 2751 2760
35. XuTHarrisonSD 1994 Mosaic analysis using FLP recombinase. Methods Cell Biol 44 655 681
36. ChangKAKurodaMI 1998 Modulation of MSL1 abundance in female Drosophila contributes to the sex specificity of dosage compensation. Genetics 150 699 709
37. PalmerMJRichmanRRichterLKurodaMI 1994 Sex-specific regulation of the male-specific lethal-1 dosage compensation gene in Drosophila. Genes Dev 8 698 706
38. SittmanDBGravesRAMarzluffWF 1983 Histone mRNA concentrations are regulated at the level of transcription and mRNA degradation. Proc Natl Acad Sci U S A 80 1849 1853
39. MarzluffWFWagnerEJDuronioRJ 2008 Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat Rev Genet 9 843 854
40. SchmittgenTDDanenbergKDHorikoshiTLenzHJDanenbergPV 1994 Effect of 5-fluoro- and 5-bromouracil substitution on the translation of human thymidylate synthase mRNA. J Biol Chem 269 16269 16275
41. WolffeAPBrownDD 1988 Developmental regulation of two 5S ribosomal RNA genes. Science 241 1626 1632
42. LarschanEAlekseyenkoAAGortchakovAAPengSLiB 2007 MSL Complex Is Attracted to Genes Marked by H3K36 Trimethylation Using a Sequence-Independent Mechanism. Mol Cell 28 121 133
43. GilfillanGDStraubTde WitEGreilFLammR 2006 Chromosome-wide gene-specific targeting of the Drosophila dosage compensation complex. Genes Dev 20 858 870
44. FagegaltierDBakerBS 2004 X Chromosome Sites Autonomously Recruit the Dosage Compensation Complex in Drosophila Males. PLoS Biol 2 e341 doi:10.1371/journal.pbio.0020341
45. ParkYMengusGBaiXKageyamaYMellerVH 2003 Sequence-specific targeting of Drosophila roX genes by the MSL dosage compensation complex. Mol Cell 11 977 986
46. KageyamaYMengusGGilfillanGKennedyHGStuckenholzC 2001 Association and spreading of the Drosophila dosage compensation complex from a discrete roX1 chromatin entry site. EMBO J 20 2236 2245
47. DengXRattnerBPSouterSMellerVH 2005 The severity of roX1 mutations is predicted by MSL localization on the X chromosome. Mech Dev 122 1094 1105
48. MedenbachJSeilerMHentzeMW 2011 Translational Control via Protein-Regulated Upstream Open Reading Frames. Cell 145 902 913
49. DuncanKGrskovicMStreinCBeckmannKNiggewegR 2006 Sex-lethal imparts a sex-specific function to UNR by recruiting it to the msl-2 mRNA 3′ UTR: translational repression for dosage compensation. Genes Dev 20 368 379
50. GrskovicMHentzeMWGebauerF 2003 A co-repressor assembly nucleated by Sex-lethal in the 3′UTR mediates translational control of Drosophila msl-2 mRNA. EMBO J 22 5571 5581
51. GebauerFGrskovicMHentzeMW 2003 Drosophila Sex-lethal inhibits the stable association of the 40S ribosomal subunit with msl-2 mRNA. Mol Cell 11 1397 1404
52. GebauerFCoronaDFPreissTBeckerPBHentzeMW 1999 Translational control of dosage compensation in Drosophila by Sex-lethal: cooperative silencing via the 5′ and 3′ UTRs of msl-2 mRNA is independent of the poly(A) tail. EMBO J 18 6146 6154
53. JohanssonAMAllgardssonAStenbergPLarssonJ 2011 msl2 mRNA is bound by free nuclear MSL complex in Drosophila melanogaster. Nucleic Acids Res 39 6428 6439
54. DuWDysonN 1999 The role of RBF in the introduction of G1 regulation during Drosophila embryogenesis. EMBO J 18 916 925
55. MacAlpineHKGordanRPowellSKHarteminkAJMacAlpineDM 2010 Drosophila ORC localizes to open chromatin and marks sites of cohesin complex loading. Genome Res 20 201 211
56. ClineTWMeyerBJ 1996 Vive la difference: males vs females in flies vs worms. Annu Rev Genet 30 637 702
57. GladsteinNMcKeonMNHorabinJI 2010 Requirement of male-specific dosage compensation in Drosophila females–implications of early X chromosome gene expression. PLoS Genet 6 e1001041 doi:10.1371/journal.pgen.1001041
58. GuttmanMAmitIGarberMFrenchCLinMF 2009 Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458 223 227
59. ZhaoJSunBKErwinJASongJJLeeJT 2008 Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322 750 756
60. MohammadFMondalTGusevaNPandeyGKKanduriC 2010 Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1. Development 137 2493 2499
61. NaganoTMitchellJASanzLAPaulerFMFerguson-SmithAC 2008 The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322 1717 1720
62. ChangWYWinegardenNAParaisoJPStevensMLWestwoodJT 2000 Visualization of nascent transcripts on Drosophila polytene chromosomes using BrUTP incorporation. Biotechniques 29 934 936
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 3
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- PIF4–Mediated Activation of Expression Integrates Temperature into the Auxin Pathway in Regulating Hypocotyl Growth
- Metabolic Profiling of a Mapping Population Exposes New Insights in the Regulation of Seed Metabolism and Seed, Fruit, and Plant Relations
- Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database
- Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders