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C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence

ABSTRACT: In blood, the transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver hematopoietic stem cells (HSCs). However, its function in adult HSCs is unknown. Here, using an inducible knockout model, we found that C/EBPa deficient adult HSCs underwent a pronounced expansion 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 C/EBPa expression correlated with its inhibitory effect on the HSC cell cycle. Mechanistically, we identified N-Myc as a C/EBPa downstream target. C/EBPa upregulation during HSC transition from an active fetal state to a quiescent adult state was accompanied by down-regulation of N-Myc, and loss of C/EBPa resulted in de-repression of NMyc. Our data establish that C/EBPa acts as a molecular switch between fetal and adult states of HSC in part via transcriptional repression of the proto-oncogene N-Myc.

ORGANISM(S): Mus musculus

PROVIDER: GSE42234 | GEO | 2012/11/14

SECONDARY ACCESSION(S): PRJNA179377

REPOSITORIES: GEO

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Project description:Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from the AGM, FL and BM. Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive line from Fetal Calvaria (OP9) and non-supportive stromal clones from fetal liver (BFC). Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from fetal liver. We took advantage of stromal clones established from the AGM, FL and BM and tested for their ability to support or not HSCs ex vivo. RNA were extracted from confluent stromal cultures or sorted cells and used for hybridization of Affymetrix (mouse gene 1.0 ST) microarrays.

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C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence

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