Rbp-Jκ controls NK cell late maturation and migration via chromatin landscape remodeling.

Authors

Hongyan Peng, Yao Yang, Yongjie Liu, Shuting Wu, Die Hu, Xiaoyu Deng, Lanlan Huang, Yana Li, Peiwen Xiong, Qinglan Yang, Songyang Li, Bowen Gong, Yabin Zhang, Liang Song, Fangjie Wang, Jianhua Yu, Zhenghui Xiao, Yafei Deng, Zhaoyang Zhong, Youcai Deng

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 36. Pages e2525481123. Sep 08, 2026. Epub Sep 01, 2026.

Abstract

The transcriptional regulator Rbp-Jκ is a pivotal molecular switch in Notch signaling; however, its cell-intrinsic role in natural killer (NK) cell maturation and migration remains incompletely understood. Here, we demonstrate that NK cell-specific deletion of Rbp-Jκ (Ncr1^iCre × Rbp-Jκ^fl/fl, Rbp-Jκ^ΔNK) impairs NK cell terminal maturation and migration, as evidenced by increased retention of NK cells in bone marrow, a reduced number of circulating NK cells and decreased expression of migration mediators (CD62L, S1pr5, and Cx3cr1). Despite exhibiting an activated phenotype, Rbp-Jκ-deficient NK cells fail to control B16F10 lung metastases in vivo because of impaired tissue mobilization. Multiomics (scRNA-seq/scATAC-seq, bulk ATAC-seq, and CUT&Tag) reveal that Rbp-Jκ orchestrates chromatin remodeling in NK cells, suppressing the expression of genes related to NK cell activation and cytotoxicity while promoting the expression of genes involved in ribosome and oxidative phosphorylation. Notably, Rbp-Jκ directly binds to the Kruppel-like factor 2 (Klf2) promoter, and loss of Rbp-Jκ reduces both the mRNA and protein levels of Klf2. Klf2 overexpression rescues the decreased expression of CD62L and CX3CR1 in Rbp-Jκ-deficient NK cells. The cooccupancy of Rbp-Jκ and Klf2 at shared genomic loci is confirmed by ChIP-qPCR. In summary, our study reveals that Rbp-Jκ acts as a master regulator of NK cell terminal maturation and tissue homing via chromatin reprogramming, with Klf2 acting as its critical downstream transcription factor.

PMID:
42679032
Bibliographic data and abstract were imported from PubMed on 02 Sep 2026.

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