Cytokine‐induced megakaryocytic differentiation is regulated by genome‐wide loss of a uSTAT transcriptional program

• Hyun Jung Park ^[1] ; Juan Li ^[1] ; Rebecca Hannah ^[1] ; Simon Biddie ^[1] ; Ana I Leal‐Cervantes ^[1] ; Kristina Kirschner ^[1] ; David Flores Santa Cruz ^[1] ; Veronika Sexl ^[2] ; Berthold Göttgens ^[1] ; Anthony R Green ^[3]
  1. [1] 1 Cambridge Institute for Medical Research Wellcome Trust/MRC Stem Cell Institute Cambridge UK; 2 Department of Haematology University of Cambridge Cambridge UK
  2. [2] 3 Institute of Pharmacology and Toxicology Veterinary University Vienna Vienna Austria
  3. [3] 1 Cambridge Institute for Medical Research Wellcome Trust/MRC Stem Cell Institute Cambridge UK; 2 Department of Haematology University of Cambridge Cambridge UK; 4 Department of Haematology Addenbrooke's Hospital Cambridge UK

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 35, Nº. 6, 2016, págs. 580-594
• Idioma: inglés
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  • Metazoan development is regulated by transcriptional networks, which must respond to extracellular cues including cytokines. The JAK/STAT pathway is a highly conserved regulatory module, activated by many cytokines, in which tyrosine‐phosphorylated STATs (pSTATs) function as transcription factors. However, the mechanisms by which STAT activation modulates lineage‐affiliated transcriptional programs are unclear. We demonstrate that in the absence of thrombopoietin (TPO), tyrosine‐unphosphorylated STAT5 (uSTAT5) is present in the nucleus where it colocalizes with CTCF and represses a megakaryocytic transcriptional program. TPO‐mediated phosphorylation of STAT5 triggers its genome‐wide relocation to STAT consensus sites with two distinct transcriptional consequences, loss of a uSTAT5 program that restrains megakaryocytic differentiation and activation of a canonical pSTAT5‐driven program which includes regulators of apoptosis and proliferation. Transcriptional repression by uSTAT5 reflects restricted access of the megakaryocytic transcription factor ERG to target genes. These results identify a previously unrecognized mechanism of cytokine‐mediated differentiation.