Zeb2 DNA-binding sites in neuroprogenitor cells reveal autoregulation and affirm neurodevelopmental defects, including in Mowat-Wilson Syndrome.

Perturbation and mechanistic studies have shown that the DNA-binding transcription factor Zeb2 controls cell fate decision and differentiation and/or maturation in multiple cell lineages in embryos and after birth. In cultured embryonic stem cells (ESCs) Zeb2s strong upregulation is necessary for the exit from primed pluripotency and for entering general and neural differentiation. We edited mouse ESCs to produce epitope-tagged Zeb2 from one of its two endogenous alleles. Using ChIP-sequencing, we mapped 2,432 DNA-binding sites of Zeb2 in ESC-derived neuroprogenitor cells (NPCs). A new, major site maps promoter-proximal to Zeb2 itself, and its homozygous removal demonstrates that Zeb2 autoregulation is necessary to elicit proper Zeb2-dependent effects in NPC differentiation. We then cross-referenced all Zeb2 DNA-binding sites with transcriptome data from Zeb2 perturbations in ESCs, ventral forebrain in mouse embryos, and adult neurogenesis from the mouse forebrain V-SVZ. While the characteristics of these neurodevelopmental systems differ, we still find interesting overlaps. This contributes to explaining neurodevelopmental disorders caused by ZEB2 deficiency, including Mowat-Wilson Syndrome.