1. The mouse KLF1 Nan variant impairs nuclear condensation and erythroid maturation
- Author
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Steven Heshusius, Frank Grosveld, Ralph Stadhouders, Marieke von Lindern, Sjaak Philipsen, Alex Maas, Nynke Gillemans, Wilfred F. J. van IJcken, Harmen J.G. van de Werken, Thamar B. van Dijk, Zeliha Ozgur, Fatemehsadat Esteghamat, Ileana Cantú, Academic Medical Center, Cell biology, Pulmonary Medicine, and Clinical Genetics
- Subjects
0301 basic medicine ,Male ,Embryology ,Embryo, Nonmammalian ,Condensation ,Cellular differentiation ,Gene Expression ,Mice ,0302 clinical medicine ,Spectrum Analysis Techniques ,Animal Cells ,hemic and lymphatic diseases ,Red Blood Cells ,Erythropoiesis ,Cells, Cultured ,Gene knockdown ,Multidisciplinary ,Chemistry ,Physics ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Animal Models ,Condensed Matter Physics ,Flow Cytometry ,Chromatin ,Cell biology ,Experimental Organism Systems ,Spectrophotometry ,Knockout mouse ,Physical Sciences ,Medicine ,Female ,Cytophotometry ,Cellular Types ,Phase Transitions ,Research Article ,Cell Physiology ,Anemia, Hemolytic ,Science ,Kruppel-Like Transcription Factors ,KLF1 ,Mouse Models ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,Erythroid Cells ,Genetics ,Animals ,Transcription factor ,Blood Cells ,Sequence Analysis, RNA ,Cell Enucleation ,Embryos ,Wild type ,Biology and Life Sciences ,DNA-binding domain ,Cell Biology ,Disease Models, Animal ,030104 developmental biology ,ran GTP-Binding Protein ,Amino Acid Substitution ,Animal Studies ,030215 immunology ,Developmental Biology - Abstract
Krüppel-like factor 1 (KLF1) is an essential transcription factor for erythroid development, as demonstrated by Klf1 knockout mice which die around E14 due to severe anemia. In humans, >140 KLF1 variants, causing different erythroid phenotypes, have been described. The KLF1 Nan variant, a single amino acid substitution (p.E339D) in the DNA binding domain, causes hemolytic anemia and is dominant over wildtype KLF1. Here we describe the effects of the KLF1 Nan variant during fetal development. We show that Nan embryos have defects in erythroid maturation. RNA-sequencing of the KLF1 Nan fetal liver cells revealed that Exportin 7 (Xpo7) was among the 782 deregulated genes. This nuclear exportin is implicated in terminal erythroid differentiation; in particular it is involved in nuclear condensation. Indeed, KLF1 Nan fetal liver cells had larger nuclei and reduced chromatin condensation. Knockdown of XPO7 in wildtype erythroid cells caused a similar phenotype. We propose that reduced expression of XPO7 is partially responsible for the erythroid defects observed in KLF1 Nan erythroid cells.
- Published
- 2019