title: LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease.
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.
authors.affiliation: Department of Haematology and Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK. dsg29@cam.ac.uk
authors.forename: Dean S
authors.initials: DS
authors.lastname: Griffiths
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dawson
authors.forename: Matthew W B
authors.initials: MW
authors.lastname: Trotter
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Cheng
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Smith
authors.forename: William
authors.initials: W
authors.lastname: Mansfield
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nichols
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bannister
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D000090266:Chromobox Protein Homolog 5; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C000715594:CBX5 protein, human; D002843:Chromatin; D006657:Histones; D053605:Leukemia Inhibitory Factor; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000090266:Chromobox Protein Homolog 5; D053614:Janus Kinase 2