Klf1-Nan Developmental Course Comparative Transcriptome

In the semi-dominant mouse model, Nan (neonatal anemia), heterozygotes suffer hemolytic anemia at birth and throughout life due to a missense mutation (E339D) in transcription factor KLF1 (Krüppel-like factor 1; formerly EKLF, erythroid Krüppel-like factor) Here, we focus on erythropoiesis in the adult spleen. We performed RNAseq in flow-sorted spleen erythroid precursors from adult Nan and WT littermates rendered anemic by phlebotomy as a means to identify global transcriptome changes specific to the Nan KLF1 defect, as opposed to those characterizing anemia generally. We show that (1) expression variation in adult Nan spleen is driven primarily by cell maturation, (2) genotype influences on gene expression are most prominent in late stages of erythroid differentiation when Klf1 expression is highest, (3) Nan-KLF1 produces tissue-specific differential gene expression, and (4) suboptimal stress and basal erythropoiesis with increased reactive oxygen species (ROS) contribute to anemia in adult Nan mice.