The mouse KLF1 Nan variant impairs nuclear condensation and erythroid maturation

Ileana Cantú; Harmen J G van de Werken; Nynke Gillemans; Ralph Stadhouders; Steven Heshusius; Alex Maas; Fatemehsadat Esteghamat; Zeliha Ozgur; Wilfred F J van IJcken; Frank Grosveld; Marieke von Lindern; Sjaak Philipsen; Thamar B van Dijk

doi:10.1371/journal.pone.0208659

The mouse KLF1 Nan variant impairs nuclear condensation and erythroid maturation

PLoS One. 2019 Mar 28;14(3):e0208659. doi: 10.1371/journal.pone.0208659. eCollection 2019.

Affiliations

¹ Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
² Department of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands.
³ Center for Biomics, Erasmus MC, Rotterdam, The Netherlands.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
Anemia, Hemolytic / genetics*
Animals
Cell Differentiation
Cells, Cultured
Chromatin / metabolism
Disease Models, Animal
Embryo, Nonmammalian / metabolism
Erythroid Cells / cytology*
Erythroid Cells / metabolism
Erythropoiesis
Female
Gene Expression Regulation, Developmental
Kruppel-Like Transcription Factors / genetics*
Male
Mice
Sequence Analysis, RNA / methods
ran GTP-Binding Protein / genetics*
ran GTP-Binding Protein / metabolism

Substances

Chromatin
Kruppel-Like Transcription Factors
RanGTP-binding protein 16
erythroid Kruppel-like factor
ran GTP-Binding Protein

Grants and funding

TvD and HvdW were supported by the Netherlands Genomics Initiative (NGI Zenith 93511036); IC, TvD, FG and SP by the Landsteiner Foundation for Blood Transfusion Research (LSBR 1040); SH, MvL and SP by the Netherlands Organization for Health Research and Development (ZonMw TOP 40-00812-98-12128); IC, TvD, FG and SP by the EU fp7 Specific Cooperation Research Project THALAMOSS (306201). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.