title: Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development.
abstract: Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Antanas
authors.initials: A
authors.lastname: Planutis
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xue
authors.affiliation: Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, MD 20892, USA.
authors.forename: Cecelia D
authors.initials: CD
authors.lastname: Trainor
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Mohan
authors.initials: M
authors.lastname: Dangeti
authors.affiliation: Mater Research Institute, University of Queensland, Woolloongabba QLD 4102, Queensland, Australia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gillinder
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.|Department of Genetics, University of Adam Mickiewicz, Poznan 61-614, Poland.
authors.forename: Miroslawa
authors.initials: M
authors.lastname: Siatecka
authors.affiliation: Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Danitza
authors.initials: D
authors.lastname: Nebor
authors.affiliation: Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Luanne L
authors.initials: LL
authors.lastname: Peters
authors.affiliation: Mater Research Institute, University of Queensland, Woolloongabba QLD 4102, Queensland, Australia.|Princess Alexandra Hospital, Brisbane QLD 4102, Queensland, Australia.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Perkins
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA james.bieker@mssm.edu.|Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.|Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.|Mindich Child Health and Development Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: James J
authors.identifier: 0000-0001-5128-7476
authors.initials: JJ
authors.lastname: Bieker
mesh_terms: D019943:Amino Acid Substitution; D000751:Anemia, Neonatal / Q000097:blood / Q000196:embryology / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000097:blood; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009124:Muscle Proteins / Q000097:blood; D050505:Mutant Proteins / Q000097:blood / Q000235:genetics; D009154:Mutation
chemical_list: D016207:Cytokines; C572502:Erfe protein, mouse; D051741:Kruppel-Like Transcription Factors; D009124:Muscle Proteins; D050505:Mutant Proteins; C080774:erythroid Kruppel-like factor; D004247:DNA
keywords: Anemia; Cytokine effects; Erythropoiesis; Monoallelic mutation; Mouse; Transcription factor