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1 Cardeza Foundation for Hematologic Research and the Division of Hematology, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, United States
2 Daniel Baugh Institute for Functional Genomics and Omputational Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
3 College of Graduate Studies, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
4 Philadelphia, Pennsylvania, United States; Cardeza Foundation for Hematologic Research and the Division of Hematology, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, United States
5 Department of Medicine, Jefferson Medical College, Cardeza Foundation for Hematologic Research and the Division of Hematology, Philadelphia, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: saul.surrey{at}jefferson.edu.
Deciphering the molecular basis for human erythropoiesis should yield information benefiting studies of the hemoglobinopathies and other erythroid disorders. We used an in vitro erythroid differentiation system to study the developing red blood cell transcriptome derived from adult CD34+ hematopoietic progenitor cells. mRNA expression profiling was used to characterize developing erythroid cells at 6 time points during differentiation (days 1, 3, 5, 7, 9, and 11). 11,763 genes (20,963 Affymetrix probe sets) were expressed on day 1 and 1504 genes, represented by 1953 probe sets, were differentially-expressed with 537 up-regulated and 969 down-regulated. A subset of the DE genes was validated using real-time RT-PCR. The differentially-expressed probe sets were subjected to a cluster metric and could be divided into 2, 3, 4, 5, or 6 clusters of genes with different expression patterns in each cluster. Genes in these clusters were examined for shared transcription factor binding sites (TFBS) in their promoters by comparing enrichment of each TFBS relative to a reference set using transcriptional regulatory network analysis. The sets of TFBS enriched in genes up- and down-regulated during erythropoiesis were distinct. This analysis identified transcriptional regulators critical to erythroid development, factors recently found to play a role as well as a new list of potential candidates, including Evi1, a potential silencer of genes up-regulated during erythropoiesis. Thus, this transcriptional regulatory network analysis has yielded a focused set of factors and their target genes whose role in differentiation of the hematopoietic stem cell into distinct blood cell lineages can be elucidated.
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