Genetic regulatory networks programming hematopoietic stem cells and erythroid lineage specification

Abstract

Erythroid cell production results from passage through cellular hierarchies dependent on differential gene expression under the control of transcription factors responsive to changing niches. We have constructed Genetic Regulatory Networks (GRNs) describing this process, based predominantly on mouse data. Regulatory network motifs identified in E. coli and yeast GRNs are found in combination in these GRNs. Feed-forward motifs with autoregulation generate forward momentum and also control its rate, which is at its lowest in hematopoietic stem cells (HSCs). The simultaneous requirement for multiple regulators in multi-input motifs (MIMs) provides tight control over expression of target genes. Combinations of MIMs, exemplified by the SCL/LMO2 complexes, which have variable content and binding sites, explain how individual regulators can have different targets in HSCs and erythroid cells and possibly also how HSCs maintain stem cell functions while expressing lineage-affiliated genes at low level, so-called multi-lineage priming. MIMs combined with cross-antagonism describe the relationship between PU.1 and GATA-1 and between two of their target genes, Fli-1 and EKLF, with victory for GATA-1 and EKLF leading to erythroid lineage specification. These GRNs are useful repositories for current regulatory information, are accessible in interactive form via the internet, enable the consequences of perturbation to be predicted, and can act as seed networks to organize the rapidly accumulating microarray data.

Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming

“…Based on their DNA-binding domain diversity (basic leucine zipper, helix-loop-helix, high-mobilitygroup, homeobox, zinc finger), it is proposed that cytokine signaling may change the transcription of globin genes through modifications in the large regulatory complexes that are localized at the globin loci. 41 Experiments involving genetic-based manipulation are underway to determine whether the transcription factors identified here directly associate with the globin locus chromatin or contribute to the cytokine-mediated changes in globin gene expression. Recently, it was demonstrated that manipulation of a small subset of transcription factors was sufficient to induce pluripotency of mammalian cells.…”

Targets of the Tal1 Transcription Factor in Erythrocytes

“…The E-box at position Ϫ1171 has an overlapping binding site for the transcription factor GATA, similar to a composite TAL1/GATA site that is present in the promoter of the GPA gene (41). The proximity of E-boxes and GATA sites is a feature frequently found in Tal1-regulated genes (42). Using the UCSC genome browser and the BLAST alignment tool (43,44), it was found that the region with the E-boxes and the GATA site is evolutionary conserved in primates, but not in mice (supplemental Fig.…”

The Dark Side of Cellular Plasticity: Stem Cells in Development and Cancer

“…Once the stem cells start the differentiation process, they begin to make reciprocally excluding lineage choices controlled by cross-antagonism between competing transcription factors, in such a way that different transcription factors, controlling different subsets of genes associated with specific lineages, are also controlling their activities in a reciprocal manner, maintaining an equilibrium that can easily be skewed towards one or the other side by external signals (Loose et al, 2007;Swiers et al, 2006). With the advent of flow cytometry and its capacity to separate cells according to defined combinations of surface markers, the study of the development of the hematopoietic system has provided enormous insight into the molecular and cellular mechanisms of lineage commitment.…”