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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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.
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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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DOI: https://doi.org/10.1038/nature09757
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