Abstract
BackgroundHematopoietic ontogeny is characterized by overlapping waves of primitive, fetal definitive, and adult definitive erythroid lineages. Our aim is to identify differences in the transcriptional control of these distinct erythroid cell maturation pathways by inferring and analyzing gene-interaction networks from lineage-specific expression datasets. Inferred networks are strongly connected and do not fit a scale-free model, making it difficult to identify essential regulators using the hub-essentiality standard.ResultsWe employed a semi-supervised machine learning approach to integrate measures of network topology with expression data to score gene essentiality. The algorithm was trained and tested on the adult and fetal definitive erythroid lineages. When applied to the primitive erythroid lineage, 144 high scoring transcription factors were found to be differentially expressed between the primitive and adult definitive erythroid lineages, including all expressed STAT-family members. Differential responses of primitive and definitive erythroblasts to a Stat3 inhibitor and IFNγ in vitro supported the results of the computational analysis. Further investigation of the original expression data revealed a striking signature of Stat1-related genes in the adult definitive erythroid network. Among the potential pathways known to utilize Stat1, interferon (IFN) signaling-related genes were expressed almost exclusively within the adult definitive erythroid network.ConclusionsIn vitro results support the computational prediction that differential regulation and downstream effectors of STAT signaling are key factors that distinguish the transcriptional control of primitive and definitive erythroid cell maturation.
Highlights
Hematopoietic ontogeny is characterized by overlapping waves of primitive, fetal definitive, and adult definitive erythroid lineages
We identified 1,080 potential transcriptional regulators expressed in the microarray expression dataset of erythroid cells using Gene Ontology (GO) annotations
Of this set of potential key factors, 16 were known to play either essential or nonessential roles in the regulation of adult definitive erythropoiesis and were used as a reference dataset for training the machine learning algorithm
Summary
Hematopoietic ontogeny is characterized by overlapping waves of primitive, fetal definitive, and adult definitive erythroid lineages. Erythroid progenitors in the bone marrow give rise to a wave of morphologically identifiable precursors that undergo a limited number of cell divisions in association with macrophage cells. These maturing erythroblasts accumulate hemoglobin, reduce cell size, condense their nucleus and enucleate to form reticulocytes that are released into the bloodstream. Primitive erythroid progenitors (EryP-CFC) first emerge in the yolk sac beginning at embryonic day 7.5 (E7.5), and generate a wave of maturing primitive erythroblasts that exclusively constitute red cells in the embryo until E12, when the fetal liver begins to release definitive erythrocytes [1]. Despite maturing in the bloodstream, primitive erythroblasts, like their definitive counterparts, enucleate to form reticulocytes [1]
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