E protein support of Zeb2 expression regulates development of multiple hematopoietic lineages

Abstract

Abstract Zeb2 is an E-box binding transcriptional repressor that were first discovered to be important for epithelial to mesenchymal transition. We recently discovered a genetic circuit involving Zeb2, Nfil3, Id2 that governs dendritic cell (DC) specification in the multipotent common dendritic cell progenitor (CDP). Nfil3 expression is required for the transition from a Zeb2hiand Id2lo stage into a Zeb2lo and Id2hi stage, which has exclusively cDC1 potential. This circuit blocks E protein activity to exclude pDC potential within the progenitor. However how E proteins regulate pDC development is still unclear. Here, we identified an enhancer element 165kb downstream of Zeb2 transcriptional starting site that can be bound by E proteins. Deletion of this enhancer completely abrogates pDC development. Interestingly, the activity of this enhancer is also required for monocytes and B cell development, while tissue resident macrophages used a different enhancer. A circuit involving Zeb2, Id2 and E proteins, where E proteins binding at this cis-element supports Zeb2 expression, is essential for lineage specification at multiple bifurcation point in the hematopoietic tree.