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Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription

Key Points

  • Dosage compensation is an epigenetic mechanism that balances gene expression from unequally distributed sex chromosomes between the sexes and in relation to the diploid autosomes. In Drosophila melanogaster, this is achieved by twofold upregulation of transcription from the single male X chromosome.

  • The modification of chromatin structure is a general principle of dosage compensation systems in various organisms. Concomitant with the evolution of sex chromosomes, pre-existing epigenetic regulators are often adapted for this novel task.

  • In D. melanogaster males, the dosage compensation complex (DCC) uses the histone acetyltransferase MOF for global hyperacetylation of X-linked chromatin at histone H4 at lysine 16 (H4K16ac). The H4K16ac modification prevents chromatin compaction and is generally associated with enhanced DNA accessibility and transcription.

  • Recognition of the X chromosome by the DCC involves the dynamic interplay between male sex lethal (MSL) proteins, male-specific RNAs on the X (roXs), and a limited number of X-specific DNA sequence elements. The DCC spreads from these high-affinity binding sites (HASs) to the transcribed regions of active genes, where it recognizes features of active chromatin such as transcription coupled histone marks.

  • The DCC induces substantial alterations in the local and long-range structure of X-linked chromatin. The resulting permissive conditions within the X-chromosomal territory create a uniquely active compartment, leading to activation even of autosomal genes that get translocated in this environment.

  • The exact mechanism of transcriptional activation remains enigmatic to date. Traditionally, transcription elongation is thought to be enhanced by H4K16ac in the transcribed regions of genes, and recent evidence supports this idea. However, some data suggest that transcriptional initiation as well as the release of paused Pol II from gene promoters might also be targeted by the dosage compensation mechanism.

Abstract

Dosage compensation is an epigenetic mechanism that normalizes gene expression from unequal copy numbers of sex chromosomes. Different organisms have evolved alternative molecular solutions to this task. In Drosophila melanogaster, transcription of the single male X chromosome is upregulated by twofold in a process orchestrated by the dosage compensation complex. Despite this conceptual simplicity, dosage compensation involves multiple coordinated steps to recognize and activate the entire X chromosome. We are only beginning to understand the intriguing interplay between multiple levels of local and long-range chromatin regulation required for the fine-tuned transcriptional activation of a heterogeneous gene population. This Review highlights the known facts and open questions of dosage compensation in D. melanogaster.

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Figure 1: Composition and localization of the dosage compensation complex.
Figure 2: DCC nucleation and spreading.
Figure 3: The X-chromosome territory represents a uniquely active compartment.
Figure 4: Hypothetical models of transcriptional regulation by the DCC.

References

  1. 1

    Ellegren, H. Sex-chromosome evolution: recent progress and the influence of male and female heterogamety. Nature Rev. Genet. 12, 157–166 (2011).

    CAS  PubMed  Google Scholar 

  2. 2

    Mank, J. E., Hosken, D. J. & Wedell, N. Some inconvenient truths about sex chromosome dosage compensation and the potential role of sexual conflict. Evolution 65, 2133–2144 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Hallacli, E. & Akhtar, A. X chromosomal regulation in flies: when less is more. Chromosome Res. 17, 603–619 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Prestel, M., Feller, C., Straub, T., Mitlohner, H. & Becker, P. B. The activation potential of MOF is constrained for dosage compensation. Mol. Cell 38, 815–826 (2010). This study describes a repressive capacity within the D. melanogaster DCC that constrains the strong MOF- and H4K16ac-mediated transcriptional activation to achieve precisely twofold enhanced expression.

    CAS  PubMed  Google Scholar 

  5. 5

    Hamada, F. N., Park, P. J., Gordadze, P. R. & Kuroda, M. I. Global regulation of X chromosomal genes by the MSL complex in Drosophila melanogaster. Genes Dev. 19, 2289–2294 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Straub, T., Gilfillan, G. D., Maier, V. K. & Becker, P. B. The Drosophila MSL complex activates the transcription of target genes. Genes Dev. 19, 2284–2288 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Park, S. W., Oh, H., Lin, Y. R. & Park, Y. MSL cis-spreading from roX gene upregulates the neighboring genes. Biochem. Biophys. Res. Commun. 399, 227–231 (2010).

    CAS  PubMed  Google Scholar 

  8. 8

    Meyer, B. J. Targeting X chromosomes for repression. Curr. Opin. Genet. Dev. 20, 179–189 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Wutz, A. Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nature Rev. Genet. 12, 542–553 (2011).

    CAS  PubMed  Google Scholar 

  10. 10

    Nguyen, D. K. & Disteche, C. M. Dosage compensation of the active X chromosome in mammals. Nature Genet. 38, 47–53 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Gupta, V. et al. Global analysis of X-chromosome dosage compensation. J. Biol. 5, 3 (2006).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Deng, X. et al. Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nature Genet. 43, 1179–1185 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Kelley, R. L. et al. Epigenetic spreading of the Drosophila dosage compensation complex from roX RNA genes into flanking chromatin. Cell 98, 513–522 (1999). This study showed that the roX1 and roX2 genes are high-affinity DCC binding sites on the X chromosome and demonstrated spreading of the DCC into chromatin surrounding an autosomal roX1 insertion. Accordingly, the 'spreading model' for DCC targeting was proposed.

    CAS  PubMed  Google Scholar 

  14. 14

    Straub, T. & Becker, P. B. Dosage compensation: the beginning and end of generalization. Nature Rev. Genet. 8, 47–57 (2007).

    CAS  Google Scholar 

  15. 15

    Steinemann, S. & Steinemann, M. Evolution of sex chromosomes: dosage compensation of the Lcp1–4 gene cluster on the evolving neo-X chromosome in Drosophila miranda. Insect Mol. Biol. 16, 167–174 (2007).

    CAS  PubMed  Google Scholar 

  16. 16

    Bashaw, G. J. & Baker, B. S. The regulation of the Drosophila msl-2 gene reveals a function for sex-lethal in translational control. Cell 89, 789–798 (1997).

    CAS  PubMed  Google Scholar 

  17. 17

    Kelley, R. L., Wang, J., Bell, L. & Kuroda, M. I. Sex lethal controls dosage compensation in Drosophila by a non-splicing mechanism. Nature 387, 195–199 (1997).

    CAS  PubMed  Google Scholar 

  18. 18

    Abaza, I., Coll., O., Patalano, S. & Gebauer, F. Drosophila UNR is required for translational repression of male-specific lethal 2 mRNA during regulation of X-chromosome dosage compensation. Genes Dev. 20, 380–389 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Duncan, K. et al. 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 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Salz, H. K. & Erickson, J. W. Sex determination in Drosophila: the view from the top. Fly 4, 60–70 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Patalano, S., Mihailovich, M., Belacortu, Y., Paricio, N. & Gebauer, F. Dual sex-specific functions of Drosophila Upstream of N-ras in the control of X chromosome dosage compensation. Development 136, 689–698 (2009).

    CAS  PubMed  Google Scholar 

  22. 22

    Kadlec, J. et al. Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1. Nature Struct. Mol. Biol. 18, 142–149 (2011). This study provides the first structural insights into the molecular interactions within the DCC by solving crystal structures of the MSL1–MSL3 as well as MSL1–MOF protein interfaces.

    CAS  Google Scholar 

  23. 23

    Morales, V. et al. Functional integration of the histone acetyltransferase MOF into the dosage compensation complex. EMBO J. 23, 2258–2268 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Bai, X., Alekseyenko, A. A. & Kuroda, M. I. Sequence-specific targeting of MSL complex regulates transcription of the roX RNA genes. EMBO J. 23, 2853–2861 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Rattner, B. P. & Meller, V. H. Drosophila male-specific lethal 2 protein controls sex-specific expression of the roX genes. Genetics 166, 1825–1832 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Li, F., Schiemann, A. H. & Scott, M. J. Incorporation of the noncoding roX RNAs alters the chromatin-binding specificity of the Drosophila MSL1–MSL2 complex. Mol. Cell Biol. 28, 1252–1264 (2008).

    CAS  PubMed  Google Scholar 

  27. 27

    Lee, C. G., Reichman, T. W., Baik, T. & Mathews, M. B. MLE functions as a transcriptional regulator of the roX2 gene. J. Biol. Chem. 279, 47740–47745 (2004).

    CAS  PubMed  Google Scholar 

  28. 28

    Aratani, S. et al. MLE activates transcription via the minimal transactivation domain in Drosophila. Int. J. Mol. Med. 21, 469–476 (2008).

    CAS  PubMed  Google Scholar 

  29. 29

    Gu, W., Wei, X., Pannuti, A. & Lucchesi, J. C. Targeting the chromatin-remodeling MSL complex of Drosophila to its sites of action on the X chromosome requires both acetyl transferase and ATPase activities. EMBO J. 19, 5202–5211 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Meller, V. H. et al. Ordered assembly of roX RNAs into MSL complexes on the dosage-compensated X chromosome in Drosophila. Curr. Biol. 10, 136–143 (2000).

    CAS  PubMed  Google Scholar 

  31. 31

    Kelley, R. L. et al. Expression of msl-2 causes assembly of dosage compensation regulators on the X chromosomes and female lethality in Drosophila. Cell 81, 867–877 (1995).

    CAS  PubMed  Google Scholar 

  32. 32

    Kind, J. et al. Genome-wide analysis reveals MOF as a key regulator of dosage compensation and gene expression in Drosophila. Cell 133, 813–828 (2008). This work showed that MOF displays a differential binding behaviour depending on its location on the male X chromosome or on autosomes and is involved in transcription regulation at gene promoters in male and female flies.

    CAS  PubMed  Google Scholar 

  33. 33

    Raja, S. J. et al. The nonspecific lethal complex is a transcriptional regulator in Drosophila. Mol. Cell 38, 827–841 (2010). This is a comprehensive study characterizing the Nonspecific lethal (NSL) complex as a novel promoter bound complex that associates with MOF.

    CAS  PubMed  Google Scholar 

  34. 34

    Kotlikova, I. V. et al. The Drosophila dosage compensation complex binds to polytene chromosomes independently of developmental changes in transcription. Genetics 172, 963–974 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Spierer, A., Begeot, F., Spierer, P. & Delattre, M. SU(VAR)3-7 links heterochromatin and dosage compensation in Drosophila. PLoS Genet. 4, e1000066 (2008).

    PubMed  PubMed Central  Google Scholar 

  36. 36

    Spierer, A., Seum, C., Delattre, M. & Spierer, P. Loss of the modifiers of variegation Su(var)3–7 or HP1 impacts male X polytene chromosome morphology and dosage compensation. J. Cell Sci. 118, 5047–5057 (2005).

    CAS  PubMed  Google Scholar 

  37. 37

    de Wit, E., Greil, F. & van Steensel, B. Genome-wide HP1 binding in Drosophila: developmental plasticity and genomic targeting signals. Genome Res. 15, 1265–1273 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Badenhorst, P., Voas, M., Rebay, I. & Wu, C. Biological functions of the ISWI chromatin remodeling complex NURF. Genes Dev. 16, 3186–3198 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Deuring, R. et al. The ISWI chromatin-remodeling protein is required for gene expression and the maintenance of higher order chromatin structure in vivo. Mol. Cell 5, 355–365 (2000).

    CAS  Google Scholar 

  40. 40

    Furuhashi, H., Nakajima, M. & Hirose, S. DNA supercoiling factor contributes to dosage compensation in Drosophila. Development 133, 4475–4483 (2006).

    CAS  Google Scholar 

  41. 41

    Jin, Y., Wang, Y., Johansen, J. & Johansen, K. M. JIL-1, a chromosomal kinase implicated in regulation of chromatin structure, associates with the male specific lethal (MSL) dosage compensation complex. J. Cell Biol. 149, 1005–1010 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Jin, Y. et al. JIL-1: a novel chromosomal tandem kinase implicated in transcriptional regulation in Drosophila. Mol. Cell 4, 129–135 (1999).

    CAS  PubMed  Google Scholar 

  43. 43

    Regnard, C. et al. Global analysis of the relationship between JIL-1 kinase and transcription. PLoS Genet. 7, e1001327 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Mendjan, S. et al. Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. Mol. Cell 21, 811–823 (2006).

    CAS  Google Scholar 

  45. 45

    Vaquerizas, J. M. et al. Nuclear pore proteins nup153 and megator define transcriptionally active regions in the Drosophila genome. PLoS Genet. 6, e1000846 (2010).

    PubMed  PubMed Central  Google Scholar 

  46. 46

    Kuroda, M. I., Kernan, M. J., Kreber, R., Ganetzky, B. & Baker, B. S. The maleless protein associates with the X chromosome to regulate dosage compensation in Drosophila. Cell 66, 935–947 (1991).

    CAS  PubMed  Google Scholar 

  47. 47

    Bell, O. et al. Accessibility of the Drosophila genome discriminates PcG repression, H4K16 acetylation and replication timing. Nature Struct. Mol. Biol. 17, 894–900 (2010). This study combined M.SssI methylation footprinting with methylated DNA immunoprecipitation to measure genome-wide DNA accessibility in D. melanogaster . Active promoters and regions that are associated with H4K16ac, particularly the male X chromosome, show high DNA accessibility, suggesting that dosage compensation is facilitated by a permissive chromatin structure.

    CAS  Google Scholar 

  48. 48

    Gu, W., Szauter, P. & Lucchesi, J. C. Targeting of MOF, a putative histone acetyl transferase, to the X chromosome of Drosophila melanogaster. Dev. Genet. 22, 56–64 (1998).

    CAS  PubMed  Google Scholar 

  49. 49

    Gelbart, M. E., Larschan, E., Peng, S., Park, P. J. & Kuroda, M. I. Drosophila MSL complex globally acetylates H4K16 on the male X chromosome for dosage compensation. Nature Struct. Mol. Biol. 16, 825–832 (2009). This study shows that almost all active genes on the male X chromosome reside within domains of high levels of H4K16ac, leading to dosage compensation of the 25% of genes that are devoid of detectable DCC binding.

    CAS  Google Scholar 

  50. 50

    Franke, A. & Baker, B. S. The rox1 and rox2 RNAs are essential components of the compensasome, which mediates dosage compensation in Drosophila. Mol. Cell 4, 117–122 (1999).

    CAS  PubMed  Google Scholar 

  51. 51

    Chu, C., Qu, K., Zhong, F. L., Artandi, S. E. & Chang, H. Y. Genomic maps of long noncoding RNA occupancy reveal principles of RNA–chromatin interactions. Mol. Cell 44, 667–678 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Akhtar, A., Zink, D. & Becker, P. B. Chromodomains are protein–RNA interaction modules. Nature 407, 405–409 (2000).

    CAS  PubMed  Google Scholar 

  53. 53

    Fauth, T., Muller-Planitz, F., Konig, C., Straub, T. & Becker, P. B. 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 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Morra, R., Yokoyama, R., Ling, H. & Lucchesi, J. C. Role of the ATPase/helicase maleless (MLE) in the assembly, targeting, spreading and function of the male-specific lethal (MSL) complex of Drosophila. Epigenet. Chromatin 4, 6 (2011).

    CAS  Google Scholar 

  55. 55

    Buscaino, A. et al. MOF-regulated acetylation of MSL-3 in the Drosophila dosage compensation complex. Mol. Cell 11, 1265–1277 (2003).

    CAS  PubMed  Google Scholar 

  56. 56

    Park, Y., Kelley, R. L., Oh, H., Kuroda, M. I. & Meller, V. H. Extent of chromatin spreading determined by roX RNA recruitment of MSL proteins. Science 298, 1620–1623 (2002).

    CAS  PubMed  Google Scholar 

  57. 57

    Kelley, R. L., Lee, O. K. & Shim, Y. K. Transcription rate of noncoding roX1 RNA controls local spreading of the Drosophila MSL chromatin remodeling complex. Mech. Dev. 125, 1009–1019 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Meller, V. H. & Rattner, B. P. The roX genes encode redundant male-specific lethal transcripts required for targeting of the MSL complex. EMBO J. 21, 1084–1091 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Kageyama, Y. et al. Association and spreading of the Drosophila dosage compensation complex from a discrete roX1 chromatin entry site. EMBO J. 20, 2236–2245 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Palmer, M. J., Richman, R., Richter, L. & Kuroda, M. I. Sex-specific regulation of the male-specific lethal-1 dosage compensation gene in Drosophila. Genes Dev. 8, 698–706 (1994).

    CAS  Google Scholar 

  61. 61

    Lyman, L. M., Copps, K., Rastelli, L., Kelley, R. L. & Kuroda, M. I. Drosophila male-specific lethal-2 protein: structure/function analysis and dependence on MSL-1 for chromosome association. Genetics 147, 1743–1753 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Alekseyenko, A. A. et al. A sequence motif within chromatin entry sites directs MSL establishment on the Drosophila X chromosome. Cell 134, 599–609 (2008). Here, authors identified a comprehensive set of X-chromosomal, high-affinity DCC binding sites by using ChIP–chip against MSL2 in an msl3 mutant background in flies.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Straub, T., Grimaud, C., Gilfillan, G. D., Mitterweger, A. & Becker, P. B. The chromosomal high-affinity binding sites for the Drosophila dosage compensation complex. PLoS Genet. 4, e1000302 (2008). Here, the authors identified a comprehensive set of X-chromosomal, high-affinity DCC binding sites by using ChIP–chip and RNAi-mediated MSL depletion in Schneider cells.

    PubMed  PubMed Central  Google Scholar 

  64. 64

    Oh, H., Bone, J. R. & Kuroda, M. I. Multiple classes of MSL binding sites target dosage compensation to the X chromosome of Drosophila. Curr. Biol. 14, 481–487 (2004).

    CAS  PubMed  Google Scholar 

  65. 65

    Dahlsveen, I. K., Gilfillan, G. D., Shelest, V. I., Lamm, R. & Becker, P. B. Targeting determinants of dosage compensation in Drosophila. PLoS Genet. 2, e5 (2006).

    PubMed  PubMed Central  Google Scholar 

  66. 66

    Gilfillan, G. D. et al. Cumulative contributions of weak DNA determinants to targeting the Drosophila dosage compensation complex. Nucleic Acids Res. 35, 3561–3572 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Gilfillan, G. D. et al. Chromosome-wide gene-specific targeting of the Drosophila dosage compensation complex. Genes Dev. 20, 858–870 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Alekseyenko, A. A., Larschan, E., Lai, W. R., Park, P. J. & Kuroda, M. I. High-resolution ChIP–chip analysis reveals that the Drosophila MSL complex selectively identifies active genes on the male X chromosome. Genes Dev. 20, 848–857 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Legube, G., McWeeney, S. K., Lercher, M. J. & Akhtar, A. X-chromosome-wide profiling of MSL-1 distribution and dosage compensation in Drosophila. Genes Dev. 20, 871–883 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Park, Y. et al. Sequence-specific targeting of Drosophila roX genes by the MSL dosage compensation complex. Mol. Cell 11, 977–986 (2003).

    CAS  PubMed  Google Scholar 

  71. 71

    van Steensel, B., Delrow, J. & Bussemaker, H. J. Genomewide analysis of Drosophila GAGA factor target genes reveals context-dependent DNA binding. Proc. Natl Acad. Sci. USA 100, 2580–2585 (2003).

    CAS  PubMed  Google Scholar 

  72. 72

    Greenberg, A. J., Yanowitz, J. L. & Schedl, P. The Drosophila GAGA factor is required for dosage compensation in males and for the formation of the male-specific-lethal complex chromatin entry site at 12DE. Genetics 166, 279–289 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Li, F., Parry, D. A. & Scott, M. J. The amino-terminal region of Drosophila MSL1 contains basic, glycine-rich, and leucine zipper-like motifs that promote X chromosome binding, self-association, and MSL2 binding, respectively. Mol. Cell. Biol. 25, 8913–8924 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Demakova, O. V. et al. The MSL complex levels are critical for its correct targeting to the chromosomes in Drosophila melanogaster. Chromosoma 112, 103–115 (2003).

    CAS  PubMed  Google Scholar 

  75. 75

    Phair, R. D. et al. Global nature of dynamic protein–chromatin interactions in vivo: three-dimensional genome scanning and dynamic interaction networks of chromatin proteins. Mol. Cell. Biol. 24, 6393–6402 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Straub, T. et al. Stable chromosomal association of MSL2 defines a dosage-compensated nuclear compartment. Chromosoma 114, 352–364 (2005).

    PubMed  Google Scholar 

  77. 77

    Strukov, Y. G., Sural, T. H., Kuroda, M. I. & Sedat, J. W. Evidence of activity-specific, radial organization of mitotic chromosomes in Drosophila. PLoS Biol. 9, e1000574 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Kind, J. & Akhtar, A. Cotranscriptional recruitment of the dosage compensation complex to X-linked target genes. Genes Dev. 21, 2030–2040 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Morra, R., Smith, E. R., Yokoyama, R. & Lucchesi, J. C. The MLE subunit of the Drosophila MSL complex uses its ATPase activity for dosage compensation and its helicase activity for targeting. Mol. Cell. Biol. 28, 958–966 (2008).

    CAS  PubMed  Google Scholar 

  80. 80

    Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006). This study demonstrated that H4K16ac prevents the condensation of a nucleosomal array into a 30 nm fibre in vitro.

    CAS  Google Scholar 

  81. 81

    Robinson, P. J. et al. 30 nm chromatin fibre decompaction requires both H4-K16 acetylation and linker histone eviction. J. Mol. Biol. 381, 816–825 (2008).

    CAS  PubMed  Google Scholar 

  82. 82

    Park, S. W., Kuroda, M. I. & Park, Y. Regulation of histone H4 Lys16 acetylation by predicted alternative secondary structures in roX noncoding RNAs. Mol. Cell. Biol. 28, 4952–4962 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Carrozza, M. J. et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123, 581–592 (2005).

    CAS  Google Scholar 

  84. 84

    Keogh, M. C. et al. Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 123, 593–605 (2005).

    CAS  Google Scholar 

  85. 85

    Larschan, E. et al. MSL complex is attracted to genes marked by H3K36 trimethylation using a sequence-independent mechanism. Mol. Cell 28, 121–133 (2007).

    CAS  PubMed  Google Scholar 

  86. 86

    Bell, O. et al. Transcription-coupled methylation of histone H3 at lysine 36 regulates dosage compensation by enhancing recruitment of the MSL complex in Drosophila melanogaster. Mol. Cell. Biol. 28, 3401–3409 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Buscaino, A., Legube, G. & Akhtar, A. X-chromosome targeting and dosage compensation are mediated by distinct domains in MSL-3. EMBO Rep. 7, 531–538 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Sural, T. H. et al. The MSL3 chromodomain directs a key targeting step for dosage compensation of the Drosophila melanogaster X chromosome. Nature Struct. Mol. Biol. 15, 1318–1325 (2008).

    CAS  Google Scholar 

  89. 89

    Moore, S. A., Ferhatoglu, Y., Jia, Y., Al-Jiab, R. A. & Scott, M. J. Structural and biochemical studies on the chromo-barrel domain of male specific lethal 3 (MSL3) reveal a binding preference for mono- or dimethyllysine 20 on histone H4. J. Biol. Chem. 285, 40879–40890 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Kim, D. et al. Corecognition of DNA and a methylated histone tail by the MSL3 chromodomain. Nature Struct. Mol. Biol. 17, 1027–1029 (2010). This study provided the first structure of an MSL protein domain bound to chromatin components. Surprisingly, the MSL3 chromobarrel domain did not interact with an H3K36me3 tail in vitro , but instead crystallized together with DNA and an H4K20me1 tail.

    CAS  Google Scholar 

  91. 91

    Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    CAS  Google Scholar 

  92. 92

    Papp, B. & Muller, J. Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins. Genes Dev. 20, 2041–2054 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Akhtar, A. & Becker, P. B. The histone H4 acetyltransferase MOF uses a C2HC zinc finger for substrate recognition. EMBO Rep. 2, 113–118 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Nielsen, P. R. et al. Structure of the chromo barrel domain from the MOF acetyltransferase. J. Biol. Chem. 280, 32326–32331 (2005).

    CAS  PubMed  Google Scholar 

  95. 95

    Grimaud, C. & Becker, P. B. The dosage compensation complex shapes the conformation of the X chromosome in Drosophila. Genes Dev. 23, 2490–2495 (2009). The first evidence for a global remodelling of higher-order X-chromosome architecture mediated by the DCC is presented in this paper. It was shown that the X-chromosomal high-affinity DCC-binding sites locate in close proximity to each other specifically in male flies. This arrangement was dependent on the presence of the core DCC subunits MSL1 and MSL2.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Grimaud, C. & Becker, P. B. Form and function of dosage-compensated chromosomes—a chicken-and-egg relationship. Bioessays 32, 709–717 (2010).

    CAS  PubMed  Google Scholar 

  97. 97

    Misteli, T. Beyond the sequence: cellular organization of genome function. Cell 128, 787–800 (2007).

    CAS  PubMed  Google Scholar 

  98. 98

    Smith, E. R., Allis, C. D. & Lucchesi, J. C. Linking global histone acetylation to the transcription enhancement of X-chromosomal genes in Drosophila males. J. Biol. Chem. 276, 31483–31486 (2001).

    CAS  Google Scholar 

  99. 99

    Lucchesi, J. C. Dosage compensation in flies and worms: the ups and downs of X-chromosome regulation. Curr. Opin. Genet. Dev. 8, 179–184 (1998).

    CAS  PubMed  Google Scholar 

  100. 100

    Larschan, E. et al. X chromosome dosage compensation via enhanced transcriptional elongation in Drosophila. Nature 471, 115–118 (2011). This study used GRO-seq in male tissue culture cells to obtain genome-wide Pol-II-binding profiles. Transcriptional elongation appeared enhanced on the compensated X chromosome, whereas Pol II passage through autosomal genes was generally less efficient.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Laverty, C., Li, F., Belikoff, E. J. & Scott, M. J. Abnormal dosage compensation of reporter genes driven by the Drosophila glass multiple reporter (GMR) enhancer-promoter. PLoS ONE 6, e20455 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Hager, G. L., McNally, J. G. & Misteli, T. Transcription dynamics. Mol. Cell 35, 741–753 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Sass, G. L., Pannuti, A. & Lucchesi, J. C. Male-specific lethal complex of Drosophila targets activated regions of the X chromosome for chromatin remodeling. Proc. Natl Acad. Sci. USA 100, 8287–8291 (2003).

    CAS  PubMed  Google Scholar 

  104. 104

    Gorchakov, A. A., Alekseyenko, A. A., Kharchenko, P., Park, P. J. & Kuroda, M. I. Long-range spreading of dosage compensation in Drosophila captures transcribed autosomal genes inserted on X. Genes Dev. 23, 2266–2271 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Wu, L., Zee, B. M., Wang, Y., Garcia, B. A. & Dou, Y. 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 (2011). This study identified D. melanogaster and mammalian MSL2 as histone H2B-directed E3 ubiquitin ligases.In mammals, H2BK34 ubiquitylation, mediated by MSL2, directly regulates H3K4 and H3K79 methylation through trans -tail crosstalk, leading to transcriptional activation of the HOXA9 and MEIS1 genes.

    PubMed  PubMed Central  Google Scholar 

  106. 106

    Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131, 58–69 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Nguyen, A. T. & Zhang, Y. The diverse functions of Dot1 and H3K79 methylation. Genes Dev. 25, 1345–1358 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Shilatifard, A. Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr. Opin. Cell Biol. 20, 341–348 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Lucchesi, J. C. The structure-function link of compensated chromatin in Drosophila. Curr. Opin. Genet. Dev. 19, 550–556 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Zippo, A. et al. Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. Cell 138, 1122–1136 (2009). This study demonstrated that MOF-mediated H4K16ac together with H3K9acS10ph can directly recruit BRD4 and PTEFb to an inducible promoter in mammalian cells, leading to facilitated promoter release of paused Pol II.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Kapoor-Vazirani, P., Kagey, J. D. & Vertino, P. M. SUV420H2-mediated H4K20 trimethylation enforces RNA polymerase II promoter-proximal pausing by blocking hMOF-dependent H4K16 acetylation. Mol. Cell. Biol. 31, 1594–1609 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Schiemann, A. H. et al. Sex-biased transcription enhancement by a 5′ tethered Gal4–MOF histone acetyltransferase fusion protein in Drosophila. BMC Mol. Biol. 11, 80 (2010).

    PubMed  PubMed Central  Google Scholar 

  113. 113

    Bhadra, M. P., Bhadra, U., Kundu, J. & Birchler, J. A. Gene expression analysis of the function of the male-specific lethal complex in Drosophila. Genetics 169, 2061–2074 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Corona, D. F. et al. ISWI regulates higher-order chromatin structure and histone H1 assembly in vivo. PLoS Biol. 5, e232 (2007).

    PubMed  PubMed Central  Google Scholar 

  115. 115

    Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Duan, Z. et al. A three-dimensional model of the yeast genome. Nature 465, 363–367 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Cremer, T. & Cremer, C. Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nature Rev. Genet. 2, 292–301 (2001).

    CAS  Google Scholar 

  118. 118

    Gondor, A. & Ohlsson, R. Chromosome crosstalk in three dimensions. Nature 461, 212–217 (2009).

    PubMed  Google Scholar 

  119. 119

    Meiklejohn, C. D., Landeen, E. L., Cook, J. M., Kingan, S. B. & Presgraves, D. C. Sex chromosome-specific regulation in the Drosophila male germline but little evidence for chromosomal dosage compensation or meiotic inactivation. PLoS Biol. 9, e1001126 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Sturgill, D., Zhang, Y., Parisi, M. & Oliver, B. Demasculinization of X chromosomes in the Drosophila genus. Nature 450, 238–241 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Parisi, M. et al. Paucity of genes on the Drosophila X chromosome showing male-biased expression. Science 299, 697–700 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Rastelli, L., Richman, R. & Kuroda, M. I. The dosage compensation regulators MLE, MSL-1 and MSL-2 are interdependent since early embryogenesis in Drosophila. Mech. Dev. 53, 223–233 (1995).

    CAS  PubMed  Google Scholar 

  123. 123

    Franke, A., Dernburg, A., Bashaw, G. J. & Baker, B. S. Evidence that MSL-mediated dosage compensation in Drosophila begins at blastoderm. Development 122, 2751–2760 (1996).

    CAS  PubMed  Google Scholar 

  124. 124

    Lott, S. E. et al. Noncanonical compensation of zygotic X transcription in early Drosophila melanogaster development revealed through single-embryo RNA-seq. PLoS Biol. 9, e1000590 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Stenberg, P. et al. Buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster. PLoS Genet. 5, e1000465 (2009).

    PubMed  PubMed Central  Google Scholar 

  126. 126

    Zhang, Y. et al. Expression in aneuploid Drosophila S2 cells. PLoS Biol. 8, e1000320 (2010).

    PubMed  PubMed Central  Google Scholar 

  127. 127

    Hartman, T. R. et al. RNA helicase A is necessary for translation of selected messenger RNAs. Nature Struct. Mol. Biol. 13, 509–516 (2006).

    CAS  Google Scholar 

  128. 128

    Robb, G. B. & Rana, T. M. RNA helicase A interacts with RISC in human cells and functions in RISC loading. Mol. Cell 26, 523–537 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Smith, E. R. et al. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Mol. Cell. Biol. 25, 9175–9188 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Taipale, M. et al. hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells. Mol. Cell. Biol. 25, 6798–6810 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Lin, H. et al. Dosage compensation in the mouse balances upregulation and silencing of X-linked genes. PLoS Biol. 5, e326 (2007).

    PubMed  PubMed Central  Google Scholar 

  132. 132

    Gupta, A. et al. The mammalian orthologue of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis. Mol. Cell. Biol. 28, 397–409 (2008).

    CAS  Google Scholar 

  133. 133

    Thomas, T., Dixon, M. P., Kueh, A. J. & Voss, A. K. Mof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture. Mol. Cell. Biol. 28, 5093–5105 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Dou, Y. et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121, 873–885 (2005).

    CAS  PubMed  Google Scholar 

  135. 135

    Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Zhou, Y. et al. Reversible acetylation of the chromatin remodelling complex NoRC is required for non-coding RNA-dependent silencing. Nature Cell Biol. 11, 1010–1016 (2009).

    CAS  PubMed  Google Scholar 

  137. 137

    Li, X., Wu, L., Corsa, C. A., Kunkel, S. & Dou, Y. Two mammalian MOF complexes regulate transcription activation by distinct mechanisms. Mol. Cell 36, 290–301 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Cai, Y. et al. Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex. J. Biol. Chem. 285, 4268–4272 (2010).

    CAS  PubMed  Google Scholar 

  139. 139

    Gupta, A. et al. Involvement of human MOF in ATM function. Mol. Cell. Biol. 25, 5292–5305 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Li, X. et al. MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. Mol. Cell. Biol. 30, 5335–5347 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Sharma, G. G. et al. MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. Mol. Cell. Biol. 30, 3582–3595 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Krishnan, V. et al. Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc. Natl Acad. Sci. USA 108, 12325–12330 (2011).

    CAS  PubMed  Google Scholar 

  143. 143

    Bird, A. W. et al. Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature 419, 411–415 (2002).

    CAS  PubMed  Google Scholar 

  144. 144

    Bhadra, M. P. et al. The role of MOF in the ionizing radiation response is conserved in Drosophila melanogaster. Chromosoma 10 Nov 2011 (doi:10.1007/s00412-011-0344-7).

    PubMed  PubMed Central  Google Scholar 

  145. 145

    Kruse, J. P. & Gu, W. MSL2 promotes Mdm2-independent cytoplasmic localization of p53. J. Biol. Chem. 284, 3250–3263 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Copps, K. et al. Complex formation by the Drosophila MSL proteins: role of the MSL2 RING finger in protein complex assembly. EMBO J. 17, 5409–5417 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Birchler, J. et al. Re-evaluation of the function of the male specific lethal complex in Drosophila. J. Genet. Genom. 38, 327–332 (2011).

    CAS  Google Scholar 

  148. 148

    Sun, X. & Birchler, J. A. Interaction study of the male specific lethal (MSL) complex and trans-acting dosage effects in metafemales of Drosophila melanogaster. Cytogenet. Genome Res. 124, 298–311 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Birchler, J. A., Yao, H. & Chudalayandi, S. Biological consequences of dosage dependent gene regulatory systems. Biochim. Biophys. Acta 1769, 422–428 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Akhtar, A. & Becker, P. B. Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol. Cell 5, 367–375 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Yokoyama, R., Pannuti, A., Ling, H., Smith, E. R. & Lucchesi, J. C. A plasmid model system shows that Drosophila dosage compensation depends on the global acetylation of histone H4 at lysine 16 and is not affected by depletion of common transcription elongation chromatin marks. Mol. Cell. Biol. 27, 7865–7870 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Schiemann, A. H. et al. The importance of location and orientation of male specific lethal complex binding sites of differing affinities on reporter gene dosage compensation in Drosophila. Biochem. Biophys. Res. Commun. 402, 699–704 (2010).

    CAS  PubMed  Google Scholar 

  153. 153

    Henry, R. A., Tews, B., Li, X. & Scott, M. J. Recruitment of the male-specific lethal (MSL) dosage compensation complex to an autosomally integrated roX chromatin entry site correlates with an increased expression of an adjacent reporter gene in male Drosophila. J. Biol. Chem. 276, 31953–31958 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank members of the laboratory for critical reading. This work was supported by the EU-funded network of excellence 'EpiGeneSys' awarded to A.A.

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Glossary

Chromosomal aneuploidy

The presence of an abnormal number of chromosomes, either more or less than the diploid number. Associated with cell and organismal inviability, cancer and birth defects.

Training data sets

The known examples of an object (for example, an exon) that are used to train prediction algorithms, so that they learn the rules for predicting an object. They can be positive training sets (consisting of true objects, such as exons) or negative training sets (consisting of false objects, such as pseudoexons).

CXC domain

A frequent protein structure module, characterized by the occurrence of one to three CXC motifs amino-terminal to a CX4CXCX6CX4–5CX2C sequence. A general role of CXC domains for DNA binding has been proposed.

Fluorescence recovery after photobleaching

(FRAP). In this technique, a laser pulse is used to bleach fluorescently labelled molecules (such as an ectopically expressed GFP fusion protein) within a restricted volume of the cell. The increase of fluorescence signal within the bleached area is then measured over time to determine diffusion rates of the labelled molecules.

30-nanometre fibres

(30 nm fibres). A helical arrangement of adjacent nucleosomes, which is believed to be the first level of chromatin compaction and appears as fibres of ~30 nm diameter in electron micrographs.

Fluorescence in situ hybridization

(FISH). A technique that uses fluorescently labelled hybridization probes to determine the abundance of RNA species or the spatial organization of genomic loci in fixed cells.

Chromosome territory

A domain of the nucleus occupied by a pair of homologous chromosomes.

Stochastic

Probabilistic; governed by chance.

Self-organizing

A process in which pattern at the global level of a system emerges solely from numerous interactions among the lower-level components of the system. The rules specifying interactions among the system's components are executed using only local information, without reference to the global pattern.

Global run-on sequencing

(GRO-seq). A method for the genome-wide mapping of the position, amount and orientation of transcriptionally engaged RNA polymerases.

Hit-and-run

Targeting mechanism in which a DNA-binding protein undergoes repeated random and short-lived interactions with DNA until it encounters its cognate binding sequence.

Deterministic

Not governed by stochastic processes.

Chromosome conformation capture

(3C). A technique that is used to study the long-distance interactions between genomic regions, which in turn can be used to study the three-dimensional architecture of chromosomes within a cell nucleus.

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Conrad, T., Akhtar, A. Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription. Nat Rev Genet 13, 123–134 (2012). https://doi.org/10.1038/nrg3124

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