Rbbp4-KO Mouse

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 epigenetic regulation, including histone modifications, which are essential for DNA replication, repair, and transcription. It is involved in multiple biological processes such as maintaining cell identity, regulating cell cycle, and influencing cell fate decisions [1,2,5,6,8].

In mouse embryonic stem cells (mESCs), auxin-induced degradation of RBBP4 reprograms mESCs to totipotent 2C-like cells, and its loss also 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 through 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 Oct4 and Sox2 expression [2]. In glioblastoma, silencing RBBP4 sensitizes cells to temozolomide, as RBBP4-p300 complex modulates the expression of pro-survival genes [3]. Also, in glioblastoma, RBBP4 promotes DNA double-strand break repair by regulating the Mre11-Rad50-NBS1 (MRN) complex, mediating chemoradiotherapy resistance [4]. In zebrafish neural progenitor cells, loss of Rbbp4 disrupts cell cycle regulation independent of Rb, leading to Tp53 acetylation and apoptosis [6]. In colon cancer, knockdown of RBBP4 inhibits cell proliferation, invasion, and migration by regulating the Wnt/β-catenin pathway [7]. In triple-negative breast cancer, RBBP4 knockdown inhibits cell proliferation, invasion, and migration by regulating epithelial-mesenchymal transition (EMT) [9].

In conclusion, Rbbp4 is essential for maintaining cell identity, regulating cell differentiation, and is involved in DNA repair and cell cycle regulation. Through gene knockout and other functional studies in mouse models and cell lines, its role in diseases such as glioblastoma, colon cancer, and triple-negative breast cancer has been revealed, providing potential therapeutic targets for these diseases.

References:

1. Ping, Wangfang, Sheng, Yingliang, Hu, Gongcheng, Pan, Guangjin, Yao, Hongjie. . RBBP4 is an epigenetic barrier for the induced transition of pluripotent stem cells into totipotent 2C-like cells. In Nucleic acids research, 51, 5414-5431. doi:10.1093/nar/gkad219. https://pubmed.ncbi.nlm.nih.gov/37021556/

2. Huang, Yikai, Su, Ting, Wang, Congcong, Jiang, Qing, Qin, Jinzhong. 2021. Rbbp4 Suppresses Premature Differentiation of Embryonic Stem Cells. In Stem cell reports, 16, 566-581. doi:10.1016/j.stemcr.2021.01.009. https://pubmed.ncbi.nlm.nih.gov/33606987/

3. Mladek, Ann C, Yan, Huihuang, Tian, Shulan, Sarkaria, Jann N, Kitange, Gaspar J. . RBBP4-p300 axis modulates expression of genes essential for cell survival and is a potential target for therapy in glioblastoma. In Neuro-oncology, 24, 1261-1272. doi:10.1093/neuonc/noac051. https://pubmed.ncbi.nlm.nih.gov/35231103/

4. Li, Junjie, Song, Chong, Gu, Junwei, Qi, Songtao, Lu, Yuntao. 2023. RBBP4 regulates the expression of the Mre11-Rad50-NBS1 (MRN) complex and promotes DNA double-strand break repair to mediate glioblastoma chemoradiotherapy resistance. In Cancer letters, 557, 216078. doi:10.1016/j.canlet.2023.216078. https://pubmed.ncbi.nlm.nih.gov/36736531/

5. Zhan, Yajing, Yin, Ankang, Su, Xiyang, Wang, Wei, Wang, Juan. 2024. Interpreting the molecular mechanisms of RBBP4/7 and their roles in human diseases (Review). In International journal of molecular medicine, 53, . doi:10.3892/ijmm.2024.5372. https://pubmed.ncbi.nlm.nih.gov/38577935/

6. Schultz-Rogers, Laura E, Thayer, Michelle L, Kambakam, Sekhar, Kool, Marcel, McGrail, Maura. 2022. Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis. In Developmental dynamics : an official publication of the American Association of Anatomists, 251, 1267-1290. doi:10.1002/dvdy.467. https://pubmed.ncbi.nlm.nih.gov/35266256/

7. Li, Yan-Dong, Lv, Zhen, Zhu, Wei-Fang. . RBBP4 promotes colon cancer malignant progression via regulating Wnt/β-catenin pathway. In World journal of gastroenterology, 26, 5328-5342. doi:10.3748/wjg.v26.i35.5328. https://pubmed.ncbi.nlm.nih.gov/32994691/

8. Cai, Lize, Liu, Bin, Cao, Yufei, Sun, Ting, Li, Yanyan. 2023. Unveiling the molecular structure and role of RBBP4/7: implications for epigenetic regulation and cancer research. In Frontiers in molecular biosciences, 10, 1276612. doi:10.3389/fmolb.2023.1276612. https://pubmed.ncbi.nlm.nih.gov/38028543/

9. Zheng, Zitong, Yao, Xu, Liu, Yi. 2022. RBBP4 plays a vital role in the malignant progression of triple-negative breast cancer by regulating epithelial-mesenchymal transition. In Genes & genomics, 44, 1301-1309. doi:10.1007/s13258-022-01262-9. https://pubmed.ncbi.nlm.nih.gov/35622231/