Abstract
Regulation of transcription is fundamental to the control of cellular gene expression and function. Although recent studies have revealed a role for the oncoprotein MYC in amplifying global transcription, little is known as to how the global transcription is suppressed. Here we report that SUMO and MYC mediate opposite effects upon global transcription by controlling the level of CDK9 sumoylation. On one hand, SUMO suppresses global transcription via sumoylation of CDK9, the catalytic subunit of P-TEFb kinase essential for productive transcriptional elongation. On the other hand, MYC amplifies global transcription by antagonizing CDK9 sumoylation. Sumoylation of CDK9 blocks its interaction with Cyclin T1 and thus the formation of active P-TEFb complex. Transcription profiling analyses reveal that SUMO represses global transcription, particularly of moderately to highly expressed genes and by generating a sumoylation-resistant CDK9 mutant, we confirm that sumoylation of CDK9 inhibits global transcription. Together, our data reveal that SUMO and MYC oppositely control global gene expression by regulating the dynamic sumoylation and desumoylation of CDK9.
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Acknowledgements
We thank Dr.Jinqiu Zhou for providing yeast RNA and Dr. Xin-Hua Feng for PIAS constructs. We thank members of Wong’s laboratory for valuable discussion. This study is supported by grants from the National Natural Science Foundation of China (81272287 and 30971640 to J.L. and 81530078 to J.W.), the Ministry of Science and Technology of China (2015CB910402 and 2017YFA0504201 to J.W.), the National Institutes of Health (CA103867 to C.M.C.), Cancer Prevention Research Institute of Texas (RP110471 and RP140367 to C.M.C.), and the Welch Foundation (I-1805 to C.M.C.). F.Y. was also supported by “Outstanding doctoral dissertation cultivation plan of action” from ECNU (PY2015037).
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F.Y., G.S., J.L. and J.W. conceived the idea for this project. F.Y., G.S., S.C., Z.W., Y.P., Z.W., D.W. designed and conducted the experiments and interpreted the data. J.C. and T.S. performed bioinformatic analysis of RNA-seq and ChIP-seq data. Y.Z performed T cell activation experiment. N.X. and J.C provided Senp1−/− and Senp2−/− MEFs and performed related experiments. L.L. carried out mass spectromic analysis of CDK9 sumoylation. S.-Y.W. and C.-M.C. performed in vitro kinase assay. J.W. and J.L. wrote the manuscript with inputs from all the other authors.
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Yu, F., Shi, G., Cheng, S. et al. SUMO suppresses and MYC amplifies transcription globally by regulating CDK9 sumoylation. Cell Res 28, 670–685 (2018). https://doi.org/10.1038/s41422-018-0023-9
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DOI: https://doi.org/10.1038/s41422-018-0023-9
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