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Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability

Nature Cell Biology volume 10, pages 489–496 (2008)Cite this article

Abstract

STAT (Signal transducer and activator of transcription) is a potent transcription factor and its aberrant activation by phosphorylation is associated with human cancers1,2,3,4. We have shown previously that overactivation of JAK, which phosphorylates STAT5,6, disrupts heterochromatin formation globally in Drosophila melanogaster7. However, it remains unclear how this effect is mediated and whether STAT is involved. Here, we demonstrate that Drosophila STAT (STAT92E) is involved in controlling heterochromatin protein 1 (HP1) distribution and heterochromatin stability. We found, unexpectedly, that loss of STAT92E, had the same effects as overactivation of JAK in disrupting heterochromatin formation and heterochromatic gene silencing, whereas overexpression of STAT92E had the opposite effects. We have further shown that the unphosphorylated or 'transcriptionally inactive' form of STAT92E is localized on heterochromatin in association with HP1, and is required for stabilizing HP1 localization and histone H3 Lys 9 methylation (H3mK9) . However, activation by phosphorylation reduces heterochromatin-associated STAT92E, causing HP1 displacement and heterochromatin destabilization. Thus, reducing levels of unphosphorylated STAT92E, either by loss of STAT92E or increased phosphorylation, causes heterochromatin instability. These results suggest that activation of STAT by phosphorylation controls both access to chromatin and activity of the transcription machinery.

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Figure 1: STAT92E is required for heterochromatic gene silencing.
Figure 2: STAT92E levels control heterochromatin abundance and HP1 localization.
Figure 3: STAT92E colocalizes and physically associates with HP1.
Figure 4: Only unphosphorylated STAT92E is localized on heterochromatin.
Figure 5: Protein-synthesis-independent heterochromatin disruption following STAT92E phosphorylation.

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Acknowledgements

We thank J. Birchler, S. Elgin, S. Hou, L. Wallrath, M. Zeidler, G. Reuter, the Developmental Hybridoma Bank (Iowa), the Bloomington Drosophila Stock Center for Drosophila strains and reagents and H. Land and D. Bohmann for helpful comments on the manuscript. This study was supported, in part, by grants from the National Institutes of Health (R01GM65774; R01GM077046), an American Cancer Society Research Scholar Grant (RSG-06-196-01-TBE) and a Leukemia & Lymphoma Society Research Scholar Grant (1087-08) to W.X.L.

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  1. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, 14642, NY, USA

    Song Shi, Kimberly Larson, Dongdong Guo, Su Jun Lim, Pranabananda Dutta, Shian-Jang Yan & Willis X. Li

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  1. Song Shi
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Contributions

W. X. L. conceived and designed the experiments; S. S., K. L., D. G., S. J. L., P. D. and S.-J. Y. performed the experiments and analysed the data; W. X. L. wrote the paper.

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Correspondence to Willis X. Li.

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Supplementary Figures S1, S2, S3, S4, S5, S6 and S7 (PDF 877 kb)

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Shi, S., Larson, K., Guo, D. et al. Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability. Nat Cell Biol 10, 489–496 (2008). https://doi.org/10.1038/ncb1713

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