LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cel
Author: ["Dean S. Griffiths","Juan Li","Mark A. Dawson","Matthew W. B. Trotter","Yi-Han Cheng","Aileen M. Smith","William Mansfield","Pentao Liu","Tony Kouzarides","Jennifer Nichols","Andrew J. Bannister","Anthony R. Green","Berthold Göttgens"]
Publication: Nature Cell Biology
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Abstract
JAK2 phosphorylates H3-Y41 residues to exclude the heterochromatin factor HP1α from chromatin. JAK2 is found to be required for maintenance of mouse embryonic stem cells through its action on the Nanog promoter. A mutant form of JAK2 associated with a myeloproliferative disorder allows embryonic stem cells to self renew in absence of cytokines. Activating mutations in the tyrosine kinase Janus kinase 2 (JAK2) cause myeloproliferative neoplasms, clonal blood stem cell disorders with a propensity for leukaemic transformation. Leukaemia inhibitory factor (LIF) signalling through the JAK-signal transducer and activator of transcription (STAT) pathway enables self-renewal of embryonic stem (ES) cells. Here we show that mouse ES cells carrying the human JAK2V617F mutation were able to self-renew in chemically defined conditions without cytokines or small-molecule inhibitors, independently of JAK signalling through the STAT3 or phosphatidylinositol-3-OH kinase pathways. Phosphorylation of histone H3 tyrosine 41 (H3Y41) by JAK2 was recently shown to interfere with binding of heterochromatin protein 1α (HP1α). Levels of chromatin-bound HP1α were lower in JAK2V617F ES cells but increased following inhibition of JAK2, coincident with a global reduction in histone H3Y41 phosphorylation. JAK2 inhibition reduced levels of the pluripotency regulator Nanog, with a reduction in H3Y41 phosphorylation and concomitant increase in HP1α levels at the Nanog promoter. Furthermore, Nanog was required for factor independence of JAK2V617F ES cells. Taken together, these results uncover a previously unrecognized role for direct signalling to chromatin by JAK2 as an important mediator of ES cell self-renewal.
Cite this article
Griffiths, D., Li, J., Dawson, M. et al. LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease. Nat Cell Biol 13, 13–21 (2011). https://doi.org/10.1038/ncb2135
