title: Robust hematopoietic progenitor cell commitment in the presence of a conflicting cue.
abstract: Hematopoietic lineage commitment is regulated by cytokines and master transcription factors, but it remains unclear how a progenitor cell chooses a lineage in the face of conflicting cues. Through transcript counting in megakaryocyte-erythroid progenitors undergoing erythropoiesis, we show that the expression levels of the pro-erythropoiesis transcription factor EKLF (also known as KLF1) and receptor EpoR are inversely correlated with their pro-megakaryopoiesis counterparts, FLI-1 and TpoR (also known as MPL). Notably, as progenitors commit to the erythrocyte lineage, EpoR is upregulated and TpoR is strongly downregulated, thus boosting the potency of the pro-erythropoiesis cue erythropoietin and effectively eliminating the activity of the pro-megakaryopoiesis cue thrombopoietin. Based on these findings, we propose a new model for exclusive decision making that explicitly incorporates signals from extrinsic cues, and we experimentally confirm a model prediction of temporal changes in transcript noise levels in committing progenitors. Our study suggests that lineage-specific receptor levels can modulate potencies of cues to achieve robust commitment decisions.
authors.affiliation: Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Najaf A
authors.initials: NA
authors.lastname: Shah
authors.affiliation: Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Marshall J
authors.initials: MJ
authors.lastname: Levesque
authors.affiliation: Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Raj
authors.affiliation: Department of Biomedical Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA csarkar@umn.edu.
authors.forename: Casim A
authors.initials: CA
authors.lastname: Sarkar
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics*; D004920:Erythropoiesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D008533:Megakaryocytes / Q000166:cytology; D051789:Proto-Oncogene Protein c-fli-1 / Q000096:biosynthesis* / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000096:biosynthesis*; D053628:Receptors, Thrombopoietin / Q000096:biosynthesis* / Q000235:genetics; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism
chemical_list: C078433:FLI1 protein, human; D051741:Kruppel-Like Transcription Factors; D051789:Proto-Oncogene Protein c-fli-1; D017467:Receptors, Erythropoietin; D053628:Receptors, Thrombopoietin; C080774:erythroid Kruppel-like factor; C082218:MPL protein, human; D013926:Thrombopoietin
keywords: Conflicting cue; Hematopoiesis; Lineage commitment