Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice.
B-cell lymphoma 11A (BCL11A) downregulation in human primary adult erythroid progenitors results in elevated expression of fetal γ-globin. Recent reports showed that BCL11A expression is activated by KLF1, leading to γ-globin repression. To study regulation of erythropoiesis and globin expression by KLF1 and BCL11A in an in vivo model, we used mice carrying a human β-globin locus transgene with combinations of Klf1 knockout, Bcl11a floxed, and EpoR(Cre) knockin alleles. We found a higher percentage of reticulocytes in adult Klf1(wt/ko) mice and a mild compensated anemia in Bcl11a(cko/cko) mice. These phenotypes were more pronounced in compound Klf1(wt/ko)::Bcl11a(cko/cko) mice. Analysis of Klf1(wt/ko), Bcl11a(cko/cko), and Klf1(wt/ko)::Bcl11a(cko/cko) mutant embryos demonstrated increased expression of mouse embryonic globins during fetal development. Expression of human γ-globin remained high in Bcl11a(cko/cko) embryos during fetal development, and this was further augmented in Klf1(wt/ko)::Bcl11a(cko/cko) embryos. After birth, expression of human γ-globin and mouse embryonic globins decreased in Bcl11a(cko/cko) and Klf1(wt/ko)::Bcl11a(cko/cko) mice, but the levels remained much higher than those observed in control animals. Collectively, our data support an important role for the KLF1-BCL11A axis in erythroid maturation and developmental regulation of globin expression.
Department of Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
Fatemehsadat
F
Esteghamat
Nynke
N
Gillemans
Ivan
I
Bilic
Emile
E
van den Akker
Ileana
I
Cantù
Teus
T
van Gent
Ursula
U
Klingmüller
Kirsten
K
van Lom
Marieke
M
von Lindern
Frank
F
Grosveld
Thamar
T
Bryn van Dijk
Meinrad
M
Busslinger
Sjaak
S
Philipsen
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian; D004920:Erythropoiesis / Q000235:genetics* / Q000502:physiology; D047109:Fetal Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D015321:Gene Rearrangement / Q000235:genetics / Q000502:physiology; D005812:Genes, Switch / Q000235:genetics* / Q000502:physiology; D005914:Globins / Q000235:genetics*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics*; D012097:Repressor Proteins; D045262:Reticulocytosis / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000196:embryology / Q000378:metabolism
C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; C080774:erythroid Kruppel-like factor; D005914:Globins