title: Combined Id1 and Id3 Deletion Leads to Severe Erythropoietic Disturbances.
abstract: The Inhibitor of DNA Binding (Id) proteins play a crucial role in regulating hematopoiesis and are known to interact with E proteins and the bHLH family of transcription factors. Current efforts seek to elucidate the individual roles of Id members in regulating hematopoietic development and specification. However, the nature of their functional redundancies remains elusive since ablation of multiple Id genes is embryonically lethal. We developed a model to test this compensation in the adult. We report that global Id3 ablation with Tie2Cre-mediated conditional ablation of Id1 in both hematopoietic and endothelial cells (Id cDKO) extends viability to 1 year but leads to multi-lineage hematopoietic defects including the emergence of anemia associated with defective erythroid development, a novel phenotype unreported in prior single Id knockout studies. We observe decreased cell counts in the bone marrow and splenomegaly to dimensions beyond what is seen in single Id knockout models. Transcriptional dysregulation of hematopoietic regulators observed in bone marrow cells is also magnified in the spleen. E47 protein levels were elevated in Id cDKO bone marrow cell isolates, but decreased in the erythroid lineage. Chromatin immunoprecipitation (ChIP) studies reveal increased occupancy of E47 and GATA1 at the promoter regions of β-globin and E2A. Bone marrow transplantation studies highlight the importance of intrinsic Id signals in maintaining hematopoietic homeostasis while revealing a strong extrinsic influence in the development of anemia. Together, these findings demonstrate that loss of Id compensation leads to dysregulation of the hematopoietic transcriptional network and multiple defects in erythropoietic development in adult mice.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Qingshi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Corey
authors.initials: C
authors.lastname: Chang
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Gonzalez
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Kamal
authors.initials: K
authors.lastname: Alzahrani
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Button
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Diego
authors.initials: D
authors.lastname: Fraidenraich
mesh_terms: D000740:Anemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004920:Erythropoiesis / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000172:deficiency* / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058127:Transcription Factor 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D058127:Transcription Factor 3; C067679:Idb3 protein, mouse