ID2 secures cDC1 specification by antagonizing E proteins at a pleiotropic Zeb2 enhancer.

ID2 promotes cDC1 development by antagonizing E proteins at Zeb2 enhancer E-boxes, rescuing cDC1 differentiation in Id2-deficient mice.

• Why it matters: Understanding how transcription factors regulate dendritic cell fate is crucial for immunology and potential therapies, yet the mechanisms remain unclear, especially regarding ID2's role.
• What they did: The study used genetic deletion of E-boxes within the Zeb2 enhancer in mice, revealing that disrupting these motifs impairs B cell and plasmacytoid dendritic cell development but enhances cDC1 differentiation, and rescues cDC1 development in Id2-deficient models.
• The result: These findings establish a two-step model of cDC1 specification involving NFIL3 and ID2, and introduce the concept of 'site-specific pleiotropy,' where different motifs within a single enhancer direct diverse cell fates.