The KLF1 transcriptional regulator is essential for normal red blood cell differentiation, and a particular mutation in this factor is associated with congenital dyserythropoietic anaemia. The Nan mutant mouse, in which the same amino acid is mutated and which displays a semi-dominant phenotype, serves as a valuable model for this disorder. It is known that the mutant protein, Nan-KLF1, can only bind a subset of target sites as compared with the wild type, and this leads to changes in downstream gene expression in heterozygous animals – due at least partly to effects of Nan-KLF1 on the target genes whose sites it can no longer bind. James Bieker and colleagues have recently discovered that the Nan-KLF1 variant can also bind a target sequence not recognised by wild-type KLF1. Now (p. 430), they investigate the phenotypic consequences of this. Importantly, they observe neomorphic expression of a number of genes in Nan/+ heterozygotes, which appears to be due to ectopic binding of Nan-KLF1 to these new target sequences. The downstream genes affected include a number of secreted factors, such as hepcidin – a regulator of cellular iron use – and interferon regulatory factor 7 (IRF7). Thus, Nan heterozygosity in the erythropoietic lineage can confer systemic effects via the inappropriate expression of secreted factors.
