Establishing the stem cell state: insights from regulatory network analysis of blood stem cell development.

Transcription factors (TFs) have long been recognized as powerful regulators of cell-type identity and differentiation. As TFs function as constituents of regulatory networks, identification and functional characterization of key interactions within these wider networks will be required to understand how TFs exert their powerful biological functions. The formation of blood cells (hematopoiesis) represents a widely used model system for the study of cellular differentiation. Moreover, specific TFs or groups of TFs have been identified to control the various cell fate choices that must be made when blood stem cells differentiate into more than a dozen distinct mature blood lineages. Because of the relative ease of accessibility, the hematopoietic system represents an attractive experimental system for the development of regulatory network models. Here, we review the modeling efforts carried out to date, which have already provided new insights into the molecular control of blood cell development. We also explore potential areas of future study such as the need for new high-throughput technologies and a focus on studying dynamic cellular systems. Many leukemias arise as the result of mutations that cause transcriptional dysregulation, thus suggesting that a better understanding of transcriptional control mechanisms in hematopoiesis is of substantial biomedical relevance. Moreover, lessons learned from regulatory network analysis in the hematopoietic system are likely to inform research on less experimentally tractable tissues.