title: Cytokine-induced megakaryocytic differentiation is regulated by genome-wide loss of a uSTAT transcriptional program.
abstract: 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.
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hannah
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Biddie
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Leal-Cervantes
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Kristina
authors.initials: K
authors.lastname: Kirschner
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Flores Santa Cruz
authors.affiliation: Institute of Pharmacology and Toxicology, Veterinary University Vienna, Vienna, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK Department of Haematology, University of Cambridge, Cambridge, UK bg200@cam.ac.uk arg1000@cam.ac.uk.
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge, UK Department of Haematology, University of Cambridge, Cambridge, UK Department of Haematology, Addenbrooke's Hospital, Cambridge, UK bg200@cam.ac.uk arg1000@cam.ac.uk.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008533:Megakaryocytes / Q000187:drug effects* / Q000502:physiology*; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D013926:Thrombopoietin / Q000378:metabolism*
chemical_list: D050799:STAT5 Transcription Factor; D013926:Thrombopoietin
keywords: JAK/STAT; cytokine; differentiation; haematopoiesis; megakaryocyte