The myeloid transcription factor Elf1 regulates genes with function in innate immunity

Transcription factor networks are critical hubs for organ development. Here we investigated the hematopoietic function of the Ets-family transcription factor Elf1 that is normally predominantly expressed in monocytes. Strikingly, Elf1 was not only a direct downstream target of HoxA9 and leukemogenic MLL fusion proteins but it was also consistently overexpressed in AML regardless of the underlying genotypic alteration. Chromatin immunoprecipitation localized Elf1 to archetypical myeloid enhancers and promoters as defined by colocalization with HoxA9 and Meis1. In perturbation/ectopic expression experiments Elf1 controlled a characteristic transcriptional program dominated by genes with a function in innate immunity. Importantly, in functional assays Elf1 was crucial for the rapid transcriptional response of myeloid cells towards lipopolysaccharide as demonstrated by upgregulation of NfkB and RelB. This activity could be assigned to genomic control elements that bound Elf1 in vitro and in vivo and it was confirmed in myelocytes with a genetic knock out of Elf1. These results give insight into the architecture of the common hematopoietic enhancer where redundant binding of transcription factors may be explained by special requirements that appear only under certain conditions. Teaser abstract Transcription factor networks are crucial control elements for hematopoietic development. Their convoluted structure and high internal redundancy complicates their functional examination. Here, Varghese et al. show that Elf1, a member of the large "Ets" (E26 transformation specific) transcription factor family with importance for normal and malignant hematopoiesis, participates in typical myeloid enhancer structures. Elf1 is involved in control of transcripts with a role in innate immunity and it is essential for the ability of myeloid cells to respond rapidly to immunologic stimuli.