期刊
EMBO JOURNAL
卷 35, 期 6, 页码 580-594出版社
WILEY
DOI: 10.15252/embj.201592383
关键词
cytokine; differentiation; haematopoiesis; JAK/STAT; megakaryocyte
资金
- Bloodwise [13003]
- Wellcome Trust [104710/Z/14/Z]
- Medical Research Council
- Kay Kendall Leukaemia Fund
- Cambridge NIHR Biomedical Research Center
- Cambridge Experimental Cancer Medicine Centre
- Leukemia and Lymphoma Society of America [07037]
- Wellcome Trust
- MRC
- EMBO
- Human Frontier Science Program
- Biotechnology and Biological Sciences Research Council [BB/I00050X/1] Funding Source: researchfish
- Cancer Research UK [12765] Funding Source: researchfish
- Medical Research Council [MC_PC_12009, MR/M008975/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10079] Funding Source: researchfish
- Wellcome Trust [104710/Z/14/Z] Funding Source: researchfish
- BBSRC [BB/I00050X/1] Funding Source: UKRI
- MRC [MR/M008975/1] Funding Source: UKRI
- Wellcome Trust [104710/Z/14/Z] Funding Source: Wellcome Trust
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 mega-karyocytic 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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