National Academy of Sciences, Proceedings of the National Academy of Sciences, 3(118), 2021
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Significance The development of lymphocytes is critical for host immunity and relies on a series of developmental checkpoints regulated by key transcription factors such as Ikaros. We hypothesized that nonprotein-coding loci might represent an additional layer of control in lymphocyte development. We identified a noncoding region (Daedalus) whose absence leads to a profound loss of Ikaros protein and a severe reduction in early lymphocyte progenitors. In contrast to Ikaros deletion, removal of Daedalus also led to an increase in red-blood-cell colony formation, suggesting that Daedalus functions as a lineage-specific stabilizer of Ikaros activity, thus acting as a “gatekeeper” of a newly identified lymphoid-erythroid checkpoint. This finding presents a paradigm potentially applicable to the control of all developmental programs.