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JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin

Abstract

Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in haematological malignancies1,2,3,4,5,6. JAK2 is a non-receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signalling cascades. Here we show that human JAK2 is present in the nucleus of haematopoietic cells and directly phosphorylates Tyr 41 (Y41) on histone H3. Heterochromatin protein 1α (HP1α), but not HP1β, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukaemic cells decreases both the expression of the haematopoietic oncogene lmo2 and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1α at the same site. These results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two genes, jak2 and lmo2, involved in normal haematopoiesis and leukaemia1,2,3,4,5,6,7,8,9.

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Figure 1: JAK2 is present in the nucleus of haematopoietic cells.
Figure 2: JAK2 phosphorylates H3Y41 in vitro and in vivo.
Figure 3: HP1α binds the Y41 region of H3 in a phosphorylation-dependent manner.
Figure 4: JAK2 signalling regulates the expression of the lmo2 oncogene.

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Acknowledgements

We thank P. Flicek, S. Wilder, B. Huntly, S. J. Dawson and all the members of the A.R.G., B.G. and T.K. laboratories, in particular P. Hurd, B. Xhemalce, E. J. Baxter and P. Beer, for helpful discussions; A. Wood for sharing unpublished data; and J. LeQuesne for help with image analysis. This work was supported by PhD fellowship grants to M.A.D. from the General Sir John Monash Foundation, the Cambridge Commonwealth Trust and Raymond and Beverly Sackler. The Green (A.R.G.) laboratory is funded by the UK Leukaemia Research Fund, the Wellcome Trust, the Leukemia & Lymphoma Society of America and the National Institute for Health Research Cambridge Biomedical Research Centre. The Göttgens (B.G.) laboratory is funded by the Leukaemia Research Fund, Cancer Research UK, the Leukemia & Lymphoma Society of America and a Medical Research Council studentship to S.D.F. The Kouzarides (T.K.) laboratory is funded by grants from Cancer Research UK and the 6th Research Framework Programme of the European Union (Epitron, HEROIC and SMARTER).

Author Contributions M.A.D. and A.J.B. designed experiments, performed research, interpreted data and wrote the manuscript. S.D.F. and T.B. performed experiments. B.G., A.R.G. and T.K. designed experiments, interpreted data and wrote the manuscript. M.A.D. and A.J.B. are joint first authors. A.R.G. and T.K. are joint senior authors.

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Correspondence to Anthony R. Green or Tony Kouzarides.

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[COMPETING INTERESTS: T.K. is a director of Abcam Ltd, and A.R.G. is on the clinical advisory board for Astex Therapeutics, Cambridge, UK. The remaining authors declare no competing interests.]

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Dawson, M., Bannister, A., Göttgens, B. et al. JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin. Nature 461, 819–822 (2009). https://doi.org/10.1038/nature08448

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