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

Park, H. J., Li, J., Hannah, R., Biddie, S., Leal‐Cervantes, A. I., Kirschner, K. , Flores Santa Cruz, D., Sexl, V., Göttgens, B. and Green, A. R. (2016) Cytokine‐induced megakaryocytic differentiation is regulated by genome‐wide loss of a uSTAT transcriptional program. EMBO Journal, 35(6), pp. 580-594. (doi:10.15252/embj.201592383) (PMID:26702099) (PMCID:PMC4801948)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kirschner, Dr Kristina
Authors: Park, H. J., Li, J., Hannah, R., Biddie, S., Leal‐Cervantes, A. I., Kirschner, K., Flores Santa Cruz, D., Sexl, V., Göttgens, B., and Green, A. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN:0261-4189
ISSN (Online):1460-2075
Published Online:23 December 2015
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in EMBO Journal 35(6):580-594
Publisher Policy:Reproduced under a Creative Commons License

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