Cytokine-induced megakaryocytic differentiation is regulated by genome-wide loss of a uSTAT transcriptional program.
EMBO J
; 35(6): 580-94, 2016 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-26702099
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trombopoetina
/
Megacariócitos
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Diferenciação Celular
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Regulação da Expressão Gênica
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Fator de Transcrição STAT5
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article