Rbbp4, or retinoblastoma binding protein 4, is a histone chaperone and a component of complexes like Polycomb repressive complex 2. It plays a crucial role in maintaining cell identity, regulating gene expression through histone modifications, and is involved in pathways related to cell fate transition, pluripotency, and cell cycle regulation [1,2,5,6,7,9]. Genetic models, such as KO/CKO mouse models, have been instrumental in studying its functions.

In mouse embryonic stem cells (mESCs), auxin-induced degradation of RBBP4 reprograms mESCs to totipotent 2C-like cells and enhances the transition to trophoblast cells. Mechanistically, RBBP4 binds to endogenous retroviruses (ERVs), recruits G9a and KAP1 to deposit H3K9me2 and H3K9me3 on ERV elements respectively, and facilitates nucleosome occupancy at ERVK and ERVL sites via CHD4 [1]. In ESCs, deficiency of RBBP4 leads to spontaneous differentiation into mesendodermal lineages, as it is essential for genomic targeting of PRC2 to a subset of developmental genes and for sustaining the expression of Oct4 and Sox2 [2]. In glioblastoma, silencing RBBP4 downregulates pro-survival genes, sensitizes cells to temozolomide, and disruption of RBBP4 enhances chemoradiotherapy sensitivity by regulating the Mre11-Rad50-NBS1 (MRN) complex [3,4]. In zebrafish neural progenitor cells, loss of Rbbp4 disrupts cell cycle regulation, leads to Tp53 acetylation and apoptosis [7]. In colon cancer and triple-negative breast cancer, knockdown of RBBP4 inhibits cell proliferation, invasion, and migration by regulating the Wnt/β-catenin pathway and epithelial-mesenchymal transition respectively [8,10].

In conclusion, Rbbp4 is essential for maintaining cell identity, pluripotency, and proper cell cycle regulation. Its dysregulation is associated with various diseases, especially cancers. The use of KO/CKO mouse models has significantly contributed to understanding its role in these biological processes and disease conditions, providing potential therapeutic targets for diseases like glioblastoma, colon cancer, and triple-negative breast cancer.