Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice

Abstract

B-cell lymphoma 11A (BCL11A) downregulation in human primary adult erythroid progenitors results in elevated expression of fetal g-globin. Recent reports showed that BCL11A expression is activated by KLF1, leading to g-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 b-globin locus transgene with combinations of Klf1 knockout, Bcl11a floxed, and EpoRCre knockin alleles. We found a higher percentage of reticulocytes in adult Klf1wt/ko mice and a mild compensated anemia in Bcl11acko/cko mice. These phenotypes were more pronounced in compound Klf1wt/ko::Bcl11acko/cko mice. Analysis of Klf1wt/ko, Bcl11acko/cko, and Klf1wt/ko::Bcl11acko/cko mutant embryos demonstrated increased expression of mouse embryonic globins during fetal development. Expression of human g-globin remained high in Bcl11acko/cko embryos during fetal development, and this was further augmented in Klf1wt/ko::Bcl11acko/cko embryos. After birth, expression of human g-globin and mouse embryonic globins decreased in Bcl11acko/cko and Klf1wt/ko::Bcl11acko/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.