title: Identification of novel hypomorphic and null mutations in Klf1 derived from a genetic screen for modifiers of α-globin transgene variegation.
abstract: Position-effect variegation of transgene expression is sensitive to the chromatin state. We previously reported a forward genetic screen in mice carrying a variegated α-globin GFP transgene to find novel genes encoding epigenetic regulators. We named the phenovariant strains "Mommes" for modifiers of murine metastable epialleles. Here we report positional cloning of mutations in two Momme strains which result in suppression of variegation. Both strains harbour point mutations in the erythroid transcription factor, Klf1. One (D11) generates a stop codon in the zinc finger domain and a homozygous null phenotype. The other (D45) generates an amino acid transversion (H350R) within a conserved linker between zinc fingers two and three. Homozygous MommeD45 mice have chronic microcytic anaemia which models the phenotype in a recently described family. This is the first genetic evidence that the linkers between the zinc fingers of transcription factors have a function beyond that of a simple spacer.
authors.affiliation: Epigenetics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
authors.forename: Anabel
authors.initials: A
authors.lastname: Sorolla
authors.affiliation: Mater-UQ Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia; School of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Tallack
authors.affiliation: La Trobe Institute for Molecular Science, Department of Genetics, La Trobe University, Bundoora, VIC 3086, Australia.
authors.forename: Harald
authors.initials: H
authors.lastname: Oey
authors.affiliation: Epigenetics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Harten
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Lucia Clemens-
authors.initials: LC
authors.lastname: Daxinger
authors.affiliation: Mater-UQ Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
authors.forename: Graham W
authors.initials: GW
authors.lastname: Magor
authors.affiliation: Epigenetics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
authors.forename: Alex N
authors.initials: AN
authors.lastname: Combes
authors.affiliation: Mater-UQ Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Ilsley
authors.affiliation: Epigenetics Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; La Trobe Institute for Molecular Science, Department of Genetics, La Trobe University, Bundoora, VIC 3086, Australia. Electronic address: E.Whitelaw@latrobe.edu.au.
authors.forename: Emma
authors.initials: E
authors.lastname: Whitelaw
authors.affiliation: Mater-UQ Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia; School of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia; Department of Cancer Services, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia. Electronic address: andrew.perkins@mater.uq.edu.au.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Perkins
mesh_terms: D000740:Anemia / Q000235:genetics; D000818:Animals; D055012:Chromosomal Position Effects; D005820:Genetic Testing / Q000379:methods; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic / Q000196:embryology / Q000235:genetics; D009154:Mutation; D013163:Splenomegaly / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics; D055542:alpha-Globins / Q000235:genetics*
chemical_list: D051741:Kruppel-Like Transcription Factors; D055542:alpha-Globins; C080774:erythroid Kruppel-like factor
keywords: EKLF; ENU mutagenesis; Epigenetics; Erythropoiesis; KLF1; Position effect variegation; Transcriptional regulation; Zinc-finger transcription factor; α-Globin