C/EBPα is required for long-term self-renewal and lineage priming of hematopoietic stem cells and for the maintenance of epigenetic configurations in multipotent progenitors

PLoS Genet. 2014 Jan;10(1):e1004079. doi: 10.1371/journal.pgen.1004079. Epub 2014 Jan 9.

Abstract

Transcription factors are key regulators of hematopoietic stem cells (HSCs) and act through their ability to bind DNA and impact on gene transcription. Their functions are interpreted in the complex landscape of chromatin, but current knowledge on how this is achieved is very limited. C/EBPα is an important transcriptional regulator of hematopoiesis, but its potential functions in HSCs have remained elusive. Here we report that C/EBPα serves to protect adult HSCs from apoptosis and to maintain their quiescent state. Consequently, deletion of Cebpa is associated with loss of self-renewal and HSC exhaustion. By combining gene expression analysis with genome-wide assessment of C/EBPα binding and epigenetic configurations, we show that C/EBPα acts to modulate the epigenetic states of genes belonging to molecular pathways important for HSC function. Moreover, our data suggest that C/EBPα acts as a priming factor at the HSC level where it actively promotes myeloid differentiation and counteracts lymphoid lineage choice. Taken together, our results show that C/EBPα is a key regulator of HSC biology, which influences the epigenetic landscape of HSCs in order to balance different cell fate options.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • CCAAT-Enhancer-Binding Protein-alpha / genetics*
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • Cell Differentiation / genetics*
  • Cell Lineage
  • Cell Proliferation
  • Epigenesis, Genetic
  • Gene Expression Regulation, Developmental
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Mice

Substances

  • CCAAT-Enhancer-Binding Protein-alpha

Associated data

  • GEO/GSE42498
  • GEO/GSE43007

Grant support

This study was supported by grants from the Danish Cancer Society (R2-A138-09-S2), the Danish Research Council for Strategic Research (0603-00202B), the German Research Council (DFG; SFB684, project A14) and through a center grant from the NovoNordisk Foundation (The Novo Nordisk Foundation Section for Stem Cell Biology in Human Disease). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.