During differentiation process, cell type specific gene expression pattern is established by orchestrate regulatory network of transcription factors (TFs). Resolving the structure of the transcriptional regulatory network (TRN) is promising way to understand the detailed mechanism of cell differentiation.
Here I estimate a transcriptional regulatory network determining the cell type specific gene expression pattern in hematopoiesis obtained from public database (GEO accession number GSE60101). Transcription factors upregulated in at least one cell type through hematopoiesis are identified as cell type specific transcription factors. It is simply assumed that the expression of the transcription factor is regulated by transcription factors of those binding motifs are enriched in its promoter region. A transcriptional regulatory network of cell type specific gene expression is estimated based on the expression profile and distribution of enriched transcription factor binding motifs in the promoter regions. The network is represented as a directional graph. And the structure of the network is analyzed based on graph theory.
Branching process where two different cell types differentiate from one progenitor through hematopoiesis is especially focused in this study. Transcriptional regulatory networks of Common Myeloid Progenitor (CMP) and Common Lymphoid Progenitor (CLP) specific gene expressions are constructed. To compare with these regulatory networks, a regulatory network of hematopoietic stem cell is also constructed as a pluripotent cell.
Through the network analysis it is clarified that the modular structure in the transcriptional regulatory network is developed through cell differentiation process. In CMP network TFs mainly regulated by Cebp family member is obviously clustered. Average expression levels of TFs in this Cebp cluster gradually increase through granulocyte differentiation. It is suggested that these TFs in Cebp cluster are myeloid lineage signature TFs. On the other hand, TFs mainly regulated by Lef1 are clustered in CLP network. Average expression levels of Lef1 cluster TFs increase in lymphoid lineage cells such as T cell and B cell. The network analysis in this study suggests that development of the modular structures composed of specific cell lineage signature TFs are critical mechanism determining cell fate.
 Chromatin state dynamics during blood formation. Science 2014 Aug 22;345(6199):943-9