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Drosophila MSL complex globally acetylates H4K16 on the male X chromosome for dosage compensation

Abstract

The Drosophila melanogaster male-specific lethal (MSL) complex binds the single male X chromosome to upregulate gene expression to equal that from the two female X chromosomes. However, it has been puzzling that 25% of transcribed genes on the X chromosome do not stably recruit MSL complex. Here we find that almost all active genes on the X chromosome are associated with robust H4 Lys16 acetylation (H4K16ac), the histone modification catalyzed by the MSL complex. The distribution of H4K16ac is much broader than that of the MSL complex, and our results favor the idea that chromosome-wide H4K16ac reflects transient association of the MSL complex, occurring through spreading or chromosomal looping. Our results parallel those of localized Polycomb repressive complex and its more broadly distributed chromatin mark, trimethylated histone H3 Lys27 (H3K27me3), suggesting a common principle for the establishment of active and silenced chromatin domains.

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Figure 1: H4K16ac is globally enriched along the male X.
Figure 2: High levels of H4K16ac are associated with transcribed genes on the male X.
Figure 3: MSL complex is required for broad H4K16ac on the male X.
Figure 4: Global H4K16ac on the male X in vivo.
Figure 5: Active genes on X and 2L are marked by 5′ H4K16ac.
Figure 6: Limited role for MOF in 5′ H4K16ac.

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Acknowledgements

We thank O. Lee (Brigham & Women's Hospital) for excellent technical assistance, A. Alekseyenko (Brigham & Women's Hospital) for male larval chromatin, A. Alekseyenko and P. Kharchenko (Children's Hospital) for helpful advice and discussions and members of the Kuroda laboratory (Brigham & Women's Hospital and Harvard Medical School) for critical reading of the manuscript. We are grateful to Y. Zhang and B. Oliver (National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health) for sharing information before publication. This work was supported by the US National Institutes of Health (GM45744 to M.I.K. and GM67825 to P.J.P.). M.E.G. is supported by the Damon Runyon Cancer Research Foundation (DRG-1913-06) and E.L. is supported by the Medical Foundation Charles A. King Trust.

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M.E.G. and E.L. performed ChIP and ChIP-chip experiments and genetic analysis of mof mutants; S.P. performed all bioinformatics analyses; P.J.P. and M.I.K. supervised the analyses; M.E.G. and M.I.K. prepared the manuscript in consultation with all co-authors.

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Correspondence to Mitzi I Kuroda.

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Gelbart, M., Larschan, E., Peng, S. et al. Drosophila MSL complex globally acetylates H4K16 on the male X chromosome for dosage compensation. Nat Struct Mol Biol 16, 825–832 (2009). https://doi.org/10.1038/nsmb.1644

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