Brd2, a member of the bromodomain and extra-terminal (BET) family, is a chromatin regulator that interprets histone Kac modification epigenetic information. It controls gene expression, remodels chromatin structures, and is involved in multiple biological processes like chromosome segregation, DNA repair, and immune system functionality [2,5]. It also plays a role in cholesterol homeostasis-related signaling [4]. Genetic models, such as gene knockout (KO) mouse models, are valuable for studying its functions.

In Glioblastoma (GBM), phosphocreatine (PCr) stabilizes Brd2, promoting epigenetic reprogramming and GBM growth. Disrupting PCr biosynthesis leads to Brd2 degradation, inhibiting tumor growth [1]. In B-cells, Brd2 deficiency impairs antibody class switch recombination, increasing DNA break end resection and aberrant recombination [2]. In C57B6/J mice, Brd2 haploinsufficiency extends lifespan and healthspan, reducing cancer incidence [3]. In mice, Brd2 knockdown in a severely obese state prevents obesity-induced inflammation, insulin resistance, and pancreatic beta-cell dysfunction, uncoupling obesity from diabetes [6].

In conclusion, Brd2 is crucial for various biological functions including epigenetic regulation, DNA repair, and immune response. KO/CKO mouse models have revealed its roles in diseases such as GBM, antibody-related immune disorders, aging-related diseases, and obesity-diabetes associations, providing potential therapeutic targets for these conditions.

References:

1. Chen, Lishu, Qi, Qinghui, Jiang, Xiaoqing, Zhou, Tao, Man, Jianghong. . Phosphocreatine Promotes Epigenetic Reprogramming to Facilitate Glioblastoma Growth Through Stabilizing BRD2. In Cancer discovery, 14, 1547-1565. doi:10.1158/2159-8290.CD-23-1348. https://pubmed.ncbi.nlm.nih.gov/38563585/

2. Gothwal, Santosh K, Refaat, Ahmed M, Nakata, Mikiyo, Honjo, Tasuku, Begum, Nasim A. . BRD2 promotes antibody class switch recombination by facilitating DNA repair in collaboration with NIPBL. In Nucleic acids research, 52, 4422-4439. doi:10.1093/nar/gkae204. https://pubmed.ncbi.nlm.nih.gov/38567724/

3. Pathak, Shilpa, Stewart, William C L, Burd, Christin E, Hester, Mark E, Greenberg, David A. 2020. Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice. In PloS one, 15, e0234910. doi:10.1371/journal.pone.0234910. https://pubmed.ncbi.nlm.nih.gov/32559200/

4. Shen, Hongtao, Li, Jing, Xie, Xiujie, Plutzky, Jorge, Guo, Lian-Wang. 2020. BRD2 regulation of sigma-2 receptor upon cholesterol deprivation. In Life science alliance, 4, . doi:10.26508/lsa.201900540. https://pubmed.ncbi.nlm.nih.gov/33234676/

5. Guo, Jiawei, Zheng, Qingquan, Peng, Yong. 2023. BET proteins: Biological functions and therapeutic interventions. In Pharmacology & therapeutics, 243, 108354. doi:10.1016/j.pharmthera.2023.108354. https://pubmed.ncbi.nlm.nih.gov/36739915/

6. Wang, Fangnian, Deeney, Jude T, Denis, Gerald V. . Brd2 gene disruption causes "metabolically healthy" obesity: epigenetic and chromatin-based mechanisms that uncouple obesity from type 2 diabetes. In Vitamins and hormones, 91, 49-75. doi:10.1016/B978-0-12-407766-9.00003-1. https://pubmed.ncbi.nlm.nih.gov/23374712/