Dataset Information

C/EBPa controls acquisition and maintenance of adult haematopoietic 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 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.

SUBMITTER: Ye M

PROVIDER: S-EPMC3781213 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Ye Min M Zhang Hong H Amabile Giovanni G Yang Henry H Staber Philipp B PB Zhang Pu P Levantini Elena E Alberich-Jordà Meritxell M Zhang Junyan J Kawasaki Akira A Tenen Daniel G DG

Nature cell biology 20130317 4

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 HSC ...[more]

PMID: 23502316

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Project description:BCOR is a component of a variant Polycomb group repressive complex 1 (PRC1) complex. Recently, we and others reported recurrent somatic BCOR loss-of-function mutations in myelodysplastic syndrome and acute myelogenous leukaemia (AML). However the role of BCOR in normal hematopoiesis is largely unknown. Here, we explored the function of BCOR in myeloid cells using myeloid murine cell models with Bcor conditional loss-of-function or overexpression alleles. Bcor mutant bone marrow cells showed significantly higher proliferation and differentiation rates with reduced protein levels of RING1B, a ubiquitin ligase subunit of PRC1 family complexes. Global RNA expression profiling in murine cells and AML patient samples with BCOR loss-of-function mutation suggested that loss of BCOR expression is associated with proliferation and myeloid differentiation and decreased stem cell quiescence. Further, we used a MLL-AF9 murine model of AML and found that loss of Bcor increased serial replating efficiency, enhanced MLL-AF9 in blocking cell differentiation, and increased expression of Evi1 which is associated with leukemic transformation. Our results strongly suggest that BCOR plays an indispensable role in maintaining hematopoietic stem cell (HSC) quiescence by inhibiting myeloid stem cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. We took advantage of a mouse conditional Bcor allele which has exons 9 and 10 been flanked by LoxP sites to allow their removal via expression of Cre recombinase. Excision of these exons results in a frame shift and a premature stop codon causing nonsense mediated decay and/or carboxy-terminal deletion of the BCOR protein. CD34+ cells were sorted from control or Bcor mutant cells cultured under myeloid stem/progenitor conditions (IL3, 6 and SCF). We used microarrays to detail the global programme of gene expression in Control and Bcor mutant CD34+ cells.

Dataset Information

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

Publications

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

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