Abstract
In blood, the transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver haematopoietic stem cells (HSCs). However, its function in adult HSCs has remained unknown. Here, using an inducible knockout model we found that C/EBPa-deficient adult HSCs underwent a pronounced increase in number with enhanced proliferation, characteristics resembling fetal liver HSCs. Consistently, transcription profiling of C/EBPa-deficient HSCs revealed a gene expression program similar to fetal liver HSCs. Moreover, we observed that age-specific Cebpa expression correlated with its inhibitory effect on the HSC cell cycle. Mechanistically we identified N-Myc as a downstream target of C/EBPa, and loss of C/EBPa resulted in de-repression of N-Myc. Our data establish C/EBPa as a central determinant in the switch from fetal to adult HSCs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult Stem Cells / cytology*
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Adult Stem Cells / physiology
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Animals
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Apoptosis
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Bone Marrow Transplantation
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CCAAT-Enhancer-Binding Proteins / physiology*
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Cell Cycle
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Cell Differentiation*
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Cell Proliferation*
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Chromatin Immunoprecipitation
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Fetal Stem Cells / cytology*
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Fetal Stem Cells / physiology
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Flow Cytometry
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Gene Expression Profiling
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / physiology
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Integrases / metabolism
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Luciferases / metabolism
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Mice
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Mice, Knockout
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Oligonucleotide Array Sequence Analysis
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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Biomarkers, Tumor
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CCAAT-Enhancer-Binding Proteins
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CEBPA protein, mouse
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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Luciferases
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Cre recombinase
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Integrases