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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 33/2/159    most recent 00127.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Fuhrken, P. G. Articles by Papoutsakis, E. T. PubMed PubMed Citation Articles by Fuhrken, P. G. Articles by Papoutsakis, E. T.

Gene Ontology-driven transcriptional analysis of CD34⁺ cell-initiated megakaryocytic cultures identifies new transcriptional regulators of megakaryopoiesis

¹ Department of Chemical and Biological Engineering
² Interdepartmental Biological Sciences Program
³ Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois
⁴ Department of Chemical Engineering and Delaware Biotechnology Institute, University of Delaware, Newark, Delaware

Differentiation of hematopoietic stem and progenitor cells is an intricate process controlled in large part at the level of transcription. While some key megakaryocytic transcription factors have been identified, the complete network of megakaryocytic transcriptional control is poorly understood. Using global gene expression microarray analysis, Gene Ontology-based functional annotations, and a novel interlineage comparison with parallel, isogenic granulocytic cultures as a negative control, we closely examined the mRNA level of transcriptional regulators in megakaryocytes derived from human mobilized peripheral blood CD34⁺ hematopoietic cells. This approach identified 199 differentially expressed transcription factors or transcriptional regulators. We identified and detailed the transcriptional kinetics of most known megakaryocytic transcription factors including GATA1, FLI1, and MAFG. Furthermore, many genes with transcription factor activity or transcription factor binding activity were identified in megakaryocytes that had not previously been associated with that lineage, including BTEB1, NR4A2, FOXO1A, MEF2C, HDAC5, VDR, and several genes associated with the tumor suppressor p53 (HIPK2, FHL2, and TADA3L). Protein expression and nuclear localization were confirmed in megakaryocytic cells for four of the novel candidate megakaryocytic transcription factors: FHL2, MXD1, E2F3, and RFX5. In light of the hypothesis that transcription factors expressed in a particular differentiation program are important contributors to such a program, these data substantially expand our understanding of transcriptional regulation in megakaryocytic differentiation of stem and progenitor cells.

gene expression; megakaryocytopoiesis; thrombopoiesis