Haematopoiesis relies on tightly controlled gene expression patterns as development proceeds through a series of progenitors. While the regulation of hematopoietic development has been well studied, the role of noncoding elements in this critical process is a developing field. In particular, the discovery of new regulators of lymphopoiesis could have important implications for our understanding of the adaptive immune system and disease. Here we elucidate how a noncoding element is capable of regulating a broadly expressed transcription factor, Ikaros, in a lymphoid lineage-specific manner, such that it imbues Ikaros with the ability to specify the lymphoid lineage over alternate fates. Deletion of the Daedalus locus, which is proximal to Ikaros, led to a severe reduction in early lymphoid progenitors, exerting control over the earliest fate decisions during lymphoid lineage commitment. Daedalus locus deletion led to alterations in Ikaros isoform expression and a significant reduction in Ikaros protein. The Daedalus locus may function through direct DNA interaction as Hi-C analysis demonstrated an interaction between the two loci. Finally, we identify an Ikaros-regulated erythroid-lymphoid checkpoint that is governed by Daedalus in a lymphoid-lineage–specific manner. Daedalus appears to act as a gatekeeper of Ikaros’s broad lineage-specifying functions, selectively stabilizing Ikaros activity in the lymphoid lineage and permitting diversion to the erythroid fate in its absence. These findings represent a key illustration of how a transcription factor with broad lineage expression must work in concert with noncoding elements to orchestrate hematopoietic lineage commitment.

随着发育通过一系列祖细胞进行，造血依赖于严格控制的基因表达模式。虽然造血发育的调节已经得到了很好的研究，但非编码元件在这个关键过程中的作用是一个发展中的领域。特别是，发现新的淋巴细胞生成调节因子可能对我们理解适应性免疫系统和疾病具有重要意义。在这里，我们阐明了非编码元件如何能够以淋巴谱系特异性方式调节广泛表达的转录因子 Ikaros，从而使 Ikaros 能够指定淋巴谱系而不是交替命运。代达罗斯的删除靠近 Ikaros 的基因座导致早期淋巴祖细胞的严重减少，从而控制了淋巴谱系确定期间最早的命运决定。Daedalus基因座缺失导致 Ikaros 同种型表达的改变和 Ikaros 蛋白的显着减少。Daedalus基因座可能通过直接的 DNA 相互作用发挥作用，因为 Hi-C 分析证明了两个基因座之间的相互作用。最后，我们确定了由代达罗斯以淋巴谱系特异性方式控制的 Ikaros 调节的红系淋巴检查点。代达罗斯似乎充当 Ikaros 广泛谱系指定功能的看门人，选择性地稳定淋巴谱系中的 Ikaros 活动，并允许在其缺席时转移到红系命运。这些发现代表了具有广泛谱系表达的转录因子如何必须与非编码元件协同工作以协调造血谱系承诺的关键说明。