C/EBPa is required for self-renewal, lineage priming and maintenance of epigenetic configurations in hematopoietic stem cells

Transcription factors are key regulators of hematopoieticstem cells (HSCs) and act through their ability to bind DNA andimpact on gene transcription. Their functions are interpreted inthe complex landscape of chromatin but current knowledge on howthis is achieved is very limited. C/EBPa is an importanttranscriptional regulator of hematopoiesis, but its potentialfunctions in HSCs have remained elusive. Here we report that C/EBPaserves to protect adult HSCs from apoptosis and to maintain theirquiescent state. Consequently, deletion of Cebpa is associatedwith loss of self-renewal and HSC exhaustion. By combining geneexpression analysis with genome-wide assessment of C/EBPa bindingand epigenetic configurations, we show that C/EBPa acts tomodulate the epigenetic states of genes belonging to molecularpathways important for HSC function. Moreover, we demonstrate thatC/EBPa acts as a priming factor at the HSC level to activelypromote myeloid differentiation and counteract lymphoid lineagechoice. Taken together our results show that C/EBPa is a keyregulator of HSC biology, which influences the epigeneticlandscape of HSCs in order to balance different cell fate options. Overall design: C/EBPaplha binding was assesed in heamatopoietic stem- and progenitor cells (LSK) and in myeloid progenitor cells (GMP) using ChIP-seq