| A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.1 and S-phase progression. | |
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MedLine Citation:
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PMID: 20877475 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hematopoietic progenitors undergo differentiation while navigating several cell division cycles, but it is unknown whether these two processes are coupled. We addressed this question by studying erythropoiesis in mouse fetal liver in vivo. We found that the initial upregulation of cell surface CD71 identifies developmentally matched erythroblasts that are tightly synchronized in S-phase. We show that DNA replication within this but not subsequent cycles is required for a differentiation switch comprising rapid and simultaneous committal transitions whose precise timing was previously unknown. These include the onset of erythropoietin dependence, activation of the erythroid master transcriptional regulator GATA-1, and a switch to an active chromatin conformation at the β-globin locus. Specifically, S-phase progression is required for the formation of DNase I hypersensitive sites and for DNA demethylation at this locus. Mechanistically, we show that S-phase progression during this key committal step is dependent on downregulation of the cyclin-dependent kinase p57(KIP2) and in turn causes the downregulation of PU.1, an antagonist of GATA-1 function. These findings therefore highlight a novel role for a cyclin-dependent kinase inhibitor in differentiation, distinct to their known function in cell cycle exit. Furthermore, we show that a novel, mutual inhibition between PU.1 expression and S-phase progression provides a "synchromesh" mechanism that "locks" the erythroid differentiation program to the cell cycle clock, ensuring precise coordination of critical differentiation events. |
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Authors:
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Ramona Pop; Jeffrey R Shearstone; Qichang Shen; Ying Liu; Kelly Hallstrom; Miroslav Koulnis; Joost Gribnau; Merav Socolovsky |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-21 |
Journal Detail:
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Title: PLoS biology Volume: 8 ISSN: 1545-7885 ISO Abbreviation: PLoS Biol. Publication Date: 2010 |
Date Detail:
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Created Date: 2010-09-29 Completed Date: 2011-01-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101183755 Medline TA: PLoS Biol Country: United States |
Other Details:
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Languages: eng Pagination: - Citation Subset: IM |
Affiliation:
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Department of Pediatrics and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, CD / metabolism Cell Cycle* Chromatin / metabolism Cyclin-Dependent Kinase Inhibitor p57 / metabolism DNA Methylation DNA Replication Down-Regulation Erythropoiesis* Mice Proto-Oncogene Proteins / metabolism* Receptors, Transferrin / metabolism S Phase* Trans-Activators / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA T32-130807/CA/NCI NIH HHS; DK32520/DK/NIDDK NIH HHS; R01 HL084168/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD; 0/CD71 antigen; 0/Chromatin; 0/Cyclin-Dependent Kinase Inhibitor p57; 0/Proto-Oncogene Proteins; 0/Receptors, Transferrin; 0/Trans-Activators; 0/proto-oncogene protein Spi-1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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