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- Title
LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease.
- Authors
Griffiths, Dean S.; Li, Juan; Dawson, Mark A.; Trotter, Matthew W. B.; Yi-Han Cheng; Smith, Aileen M.; Mansfield, William; Liu, Pentao; Kouzarides, Tony; Nichols, Jennifer; Bannister, Andrew J.; Green, Anthony R.; Göttgens, Berthold
- Abstract
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.
- Subjects
PROTEIN-tyrosine kinases; LEUKEMIA inhibitory factor; CHROMATIN; EMBRYONIC stem cells; STEM cells; HISTONES; PHOSPHORYLATION; DISEASES
- Publication
Nature Cell Biology, 2011, Vol 13, Issue 1, p13
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb2135