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X chromosome dosage compensation via enhanced transcriptional elongation in Drosophila

Abstract

The evolution of sex chromosomes has resulted in numerous species in which females inherit two X chromosomes but males have a single X, thus requiring dosage compensation. MSL (Male-specific lethal) complex increases transcription on the single X chromosome of Drosophila males to equalize expression of X-linked genes between the sexes1. The biochemical mechanisms used for dosage compensation must function over a wide dynamic range of transcription levels and differential expression patterns. It has been proposed2 that the MSL complex regulates transcriptional elongation to control dosage compensation, a model subsequently supported by mapping of the MSL complex and MSL-dependent histone 4 lysine 16 acetylation to the bodies of X-linked genes in males, with a bias towards 3′ ends3,4,5,6,7. However, experimental analysis of MSL function at the mechanistic level has been challenging owing to the small magnitude of the chromosome-wide effect and the lack of an in vitro system for biochemical analysis. Here we use global run-on sequencing (GRO-seq)8 to examine the specific effect of the MSL complex on RNA Polymerase II (RNAP II) on a genome-wide level. Results indicate that the MSL complex enhances transcription by facilitating the progression of RNAP II across the bodies of active X-linked genes. Improving transcriptional output downstream of typical gene-specific controls may explain how dosage compensation can be imposed on the diverse set of genes along an entire chromosome.

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Figure 1: The male X chromosome has higher levels of engaged RNAP II over gene bodies relative to autosomes.
Figure 2: The MSL complex increases engaged RNAP II density on the male X chromosome.
Figure 3: The MSL complex facilitates the progression of engaged RNAP II across transcription units.
Figure 4: MSL function correlates with the presence of H4K16 acetylation.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Data are deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession numbers GSE25321 and GSE25887.

References

  1. 1

    Gelbart, M. E. & Kuroda, M. I. Drosophila dosage compensation: a complex voyage to the X chromosome. Development 136, 1399–1410 (2009)

    CAS  Article  Google Scholar 

  2. 2

    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  Article  Google Scholar 

  3. 3

    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  Article  Google Scholar 

  4. 4

    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  Article  Google Scholar 

  5. 5

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

    CAS  Article  Google Scholar 

  6. 6

    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)

    CAS  Article  Google Scholar 

  7. 7

    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)

    CAS  Article  Google Scholar 

  8. 8

    Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008)

    ADS  CAS  Article  Google Scholar 

  9. 9

    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  Article  Google Scholar 

  10. 10

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

    Article  Google Scholar 

  11. 11

    Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nature Genet. 39, 1507–1511 (2007)

    CAS  Article  Google Scholar 

  12. 12

    Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nature Genet. 39, 1512–1516 (2007)

    CAS  Article  Google Scholar 

  13. 13

    Belote, J. M. & Lucchesi, J. C. Male-specific lethal mutations of Drosophila melanogaster. Genetics 96, 165–186 (1980)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    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  Article  Google Scholar 

  15. 15

    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  Article  Google Scholar 

  16. 16

    Hilfiker, A., Hilfiker-Kleiner, D., Pannuti, A. & Lucchesi, J. C. 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 (1997)

    CAS  Article  Google Scholar 

  17. 17

    Wang, Z. et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nature Genet. 40, 897–903 (2008)

    CAS  Article  Google Scholar 

  18. 18

    Kaplan, C. D., Laprade, L. & Winston, F. Transcription elongation factors repress transcription initiation from cryptic sites. Science 301, 1096–1099 (2003)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Mavrich, T. N. et al. Nucleosome organization in the Drosophila genome. Nature 453, 358–362 (2008)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Mavrich, T. N. et al. A barrier nucleosome model for statistical positioning of nucleosomes throughout the yeast genome. Genome Res. 18, 1073–1083 (2008)

    CAS  Article  Google Scholar 

  21. 21

    Belotserkovskaya, R. et al. FACT facilitates transcription-dependent nucleosome alteration. Science 301, 1090–1093 (2003)

    ADS  CAS  Article  Google Scholar 

  22. 22

    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  Article  Google Scholar 

  23. 23

    Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006)

    ADS  CAS  Article  Google Scholar 

  24. 24

    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)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Oh, H., Park, Y. & Kuroda, M. I. Local spreading of MSL complexes from roX genes on the Drosophila X chromosome. Genes Dev. 17, 1334–1339 (2003)

    CAS  Article  Google Scholar 

  26. 26

    Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

    Article  Google Scholar 

  27. 27

    Nechaev, S. et al. Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science 327, 335–338 (2010)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Rozowsky, J. et al. PeakSeq enables systematic scoring of ChIP-seq experiments relative to controls. Nature Biotechnol. 27, 66–75 (2009)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank F. M. Winston, S. Buratowski, A. Alekseyenko, M. Gelbart, C. Wang and A. Gortchakov for comments on the manuscript, and are grateful to N. Gehlenborg for graphic design expertise. This work was supported by the following NIH grants: GM45744 (M.I.K.), GM082798 (P.J.P.) and HG4845 (J.T.L.). E.L. was supported by a Charles A. King Trust fellowship from the Medical Foundation.

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E.L. performed the experiments and E.P.B. and P.V.K. performed the computational analyses. P.J.P. advised on the computational analyses and the manuscript preparation. L.J.C., J.T.L. and M.I.K. advised on experimental protocols and/or design. E.L. and M.I.K. prepared the manuscript.

Corresponding authors

Correspondence to Peter J. Park or Mitzi I. Kuroda.

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The file contains Supplementary Figures 1-10 with legends, Supplementary Tables 1-3 and additional references. (PDF 13927 kb)

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Larschan, E., Bishop, E., Kharchenko, P. et al. X chromosome dosage compensation via enhanced transcriptional elongation in Drosophila. Nature 471, 115–118 (2011). https://doi.org/10.1038/nature09757

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