TY - JOUR
T1 - The mouse KLF1 Nan variant impairs nuclear condensation and erythroid maturation
AU - Cantú, Ileana
AU - van de Werken, Harmen J. G.
AU - Gillemans, Nynke
AU - Stadhouders, Ralph
AU - Heshusius, Steven
AU - Maas, Alex
AU - Esteghamat, Fatemehsadat
AU - Ozgur, Zeliha
AU - van IJcken, Wilfred F. J.
AU - Grosveld, Frank
AU - von Lindern, Marieke
AU - Philipsen, Sjaak
AU - van Dijk, Thamar B.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063681048&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30921348
U2 - https://doi.org/10.1371/journal.pone.0208659
DO - https://doi.org/10.1371/journal.pone.0208659
M3 - Article
C2 - 30921348
SN - 1932-6203
VL - 14
JO - PLOS ONE
JF - PLOS ONE
IS - 3
M1 - e0208659
ER -