Transcriptional regulation of haematopoietic transcription factors

Haematopoiesis represents one of the best studied models of adult stem cell development and differentiation [1,2]. Powerful techniques allow purification and in vitro as well as in vivo functional assays of small subsets of cells, from haematopoietic stem cells (HSCs) via a plethora of intermediate progenitors to fully mature cell types. Transcription factors (TFs) directly regulate gene expression and thus control cellular phenotypes. It is no surprise, therefore, that TFs have emerged as some of the most powerful regulators of both normal development and disease.TFs play important roles during haematopoiesis, from stem cell maintenance to lineage commitment and differentiation. However, relatively little is known about the way in which regulatory information is encoded in the genome, and how individual TFs are integrated into wider regulatory networks. Based on the recent analysis of large-scale efforts to reconstruct tissue-specific regulatory networks, it has been suggested that transcriptional regulatory networks are characterised by a high degree of connectivity between TFs and transcriptional cofactors. Extensive cross- and autoregulatory links therefore create densely connected regulatory circuits that control the large numbers of tissue-specific effector proteins (en-zymes, structural proteins) [3,4] (Figure 1). To understand the functionality of large mammalian regulatory networks, it will therefore be important to identify downstream target genes of specific TFs as well as gain insight into combinatorial TF interactions. This in turn will not only provide fundamental insights into normal development, but also advance our understanding of how deregulation of networks contributes to pathology.The cis-regulatory regions of a gene locus can be thought of as different modules, each partaking in an important role, such as driving expression of the gene to a specific subset of cells or a specific tissue type. The activity of each regulatory region is controlled