Modeling and identification of a gene regulatory network programming erythropoiesis (1)

The development of mature blood cells of distinct lineages from the hematopoietic stem cells (hematopoiesis) involves a progressive restriction of differentiation potential and the establishment of lineage-specific gene expression profiles. The establishment of these profiles relies on lineage-specific transcription factors to modulate the expression of their target genes. This work is embedded in a wider ErasmusMC/CWI collaboration that develops the informatics and mathematics to underpin studies on gene expression regulation by mapping and analyzing the regulatory pathways and networks of transcription factors that control cellular functions (so called 'Gene Regulatory Networks' or 'GRNs'). This project is concerned with the mathematical part and concentrates on a GRN central to erythropoiesis. Among the many housekeeping and tissue-specific genes involved in the differentiation and the commitment of hematopoietic stem cells to erythrocytes (erythropoiesis), we focus on a small pool of genes (Gata-1, Gata-2, Pu.1, EKLF, FOG-1, alpha/beta-globin) known to be critically involved in an intricate but well-less investigated regulatory circuit. Based on the regulatory interactions in the GRN we have developed models in the form of a system to account for the dynamics of gene expression and regulation involved in this process. Because of the lack of information about a significant number of model parameters, our focus is on system identification. In this first report some preliminary results are presented based on synthetic data. However, time series of the levels of all relevant mRNA’s are available from micro-array analysis of G1E cells, a murine cell line which recapitulates erythropoiesis. In the follow-up report a detailed account will be given of the parameter estimation and identifiability analysis with respect to these data. This will eventually allow for a thorough evaluation of the role of various characterized as well as hypothetical regulatory mechanisms. In depth characterization of the necessary expression patterns and gene regulatory interactions responsible for the the set of commitments all along the erythroid lineage is essential to gain fundamental insight into the behaviour of these complex networks and to design further experiments. Ultimately, this may lead to ways to rescue erythroid differentiation in several anemic diseases.