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

Authors

Feiya Ou, Tian-Tian Liu, Siling Du, Jing Chen, Magdalena Kraft, Giri Nam, Bishan Bhattarai, Hyeyoon Shin, Alyssa R Koch, Theresa L Murphy, Kenneth M Murphy

Published in

Nature immunology. Aug 25, 2026. Epub Aug 25, 2026.

Abstract

The transcriptional regulator ID2 is required for type 1 classical dendritic cell (cDC1) specification, yet the mechanism has remained obscure. We previously identified the Zeb2 -165-kb enhancer as key to normal hematopoiesis, controlled by competing CEBP and NFIL3 inputs during myeloid dendritic cell divergence. Here we uncover an unprecedented role for E proteins in myelopoiesis and demonstrate that ID2 promotes cDC1 development by antagonizing E protein activity at E-boxes within the Zeb2 enhancer. Deleting these E-boxes abolishes B cell and plasmacytoid dendritic cell development while skewing myelopoiesis toward cDC1s. Remarkably, E-box deletion rescues cDC1 development in Id2-deficient mice. These findings support a two-step model in which NFIL3 transiently represses Zeb2, followed by ID2-mediated inhibition of E proteins to stabilize cDC1 fate specification. Further, this work defines a paradigm of 'site-specific pleiotropy', wherein distinct transcription factor motifs-E-boxes and CEBP sites-within a single enhancer direct diverse cell fates.

PMID:
42642670
Bibliographic data and abstract were imported from PubMed on 26 Aug 2026.

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