Alternative titles; symbols
HGNC Approved Gene Symbol: BRD2
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38) : 6:32,968,594-32,981,505 (from NCBI)
The nuclear kinase BRD2 is a component of a signal transduction pathway involved in development and growth control (Denis and Green, 1996).
In a search for novel genes in the human major histocompatibility complex (MHC) class II region on chromosome 6p21.3, Okamoto et al. (1991) and Beck et al. (1992) identified a gene that they termed RING3. ('RING' is an acronym for 'really interesting new gene.') Based on mapping and genomic sequencing, RING3 was located in the middle of the class II region between the genes HLA-DNA (142930) and HLA-DMA (142855). In contrast to all the other genes encoded in the class II region, RING3 appeared to have no obvious function associated with the immune system based on sequence comparisons. The striking sequence similarity to the female sterile homeotic (fsh) gene in Drosophila, however, suggested a conserved biologic function for RING3.
Denis and Green (1996) discovered that the RING3 product is, in fact, a mitogen-activated nuclear kinase involved in signal transduction and that it is upregulated in certain types of leukemia.
With the aim of learning more about the phylogeny of RING3, Thorpe et al. (1996) identified further homologs in different species and determined their gene structures. The functional analysis of RING3 had been further complicated by the finding of a second, non-MHC-linked copy of RING3 in humans by Nomura et al. (1994). This was referred to by them as ORFX (601541).
Okamoto et al. (1991) identified the BRD2 gene in the MHC class II region on chromosome 6p21.
Dawson et al. (2011) demonstrated that I-BET151, a novel small molecule inhibitor of the BET family, of which BRD2 is a member, has profound efficacy against human and murine MLL-fusion leukemia cell lines through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in 2 human leukemia cell lines with different MLL fusions altered the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes BCL2 (151430), C-MYC (190080), and CDK6 (603368) through the displacement of BRD3/4, PAFc, and SEC components from chromatin. In vivo studies indicated that I-BET151 has significant therapeutic value, providing survival benefit in 2 distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukemia.
Xie et al. (2022) found that depletion of the cohesin complex component Rad21 (606462) triggered spatial mixing of accessible chromatin domains (ACDs) without affecting their compaction in mouse embryonic stem cells (ESCs). Moreover, spatial mixing of ACDs was independent of transcription, but it involved the BET protein family. Depletion analysis in mouse ESCs identified Brd2 as a BET protein involved in organizing accessible chromatin and showed that Brd2 maintained compaction of ACDs and promoted their interactions in the absence of cohesin. The interplay between Brd2 and cohesin regulated genome topology in the nucleus, and cohesin antagonized Brd2 binding to chromatin and counteracted its ability to promote interactions between ACDs. In the absence of cohesin, the affinity of Brd2 for active chromatin increased. In addition to cohesin, Brd4 (608749) competed with Brd2 to inhibit its activities in genome organization, implying a division of labor for BET proteins to govern distinct regulatory processes in the accessible genome. Polymer simulation supported a model of Brd2-cohesin interplay for nuclear topology, where genome compartmentalization resulted from competition between loop extrusion and chromatin state-specific affinity interactions.
For discussion of a possible association between variation in the BRD2 gene and juvenile myoclonic epilepsy, see EJM3 (608816).
Beck, S., Hanson, I., Kelly, A., Pappin, D. J., Trowsdale, J. A homologue of the Drosophila female sterile homeotic (fsh) gene in the class II region of the human MHC. DNA Seq. 2: 203-210, 1992. [PubMed: 1352711] [Full Text: https://doi.org/10.3109/10425179209020804]
Dawson, M. A., Prinjha, R. K., Dittmann, A., Giotopoulos, G., Bantscheff, M., Chan, W.-I., Robson, S. C., Chung, C., Hopf, C., Savitski, M. M., Huthmacher, C., Gudgin, E., and 15 others. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478: 529-533, 2011. [PubMed: 21964340] [Full Text: https://doi.org/10.1038/nature10509]
Denis, G. V., Green, M. R. A novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulator. Genes Dev. 10: 261-271, 1996. [PubMed: 8595877] [Full Text: https://doi.org/10.1101/gad.10.3.261]
Nomura, N., Nagase, T., Miyajima, N., Sazuka, T., Tanaka, A., Sato, S., Seki, N., Kawarabayasi, Y., Ishikawa, K., Tabata, S. Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 1: 223-229, 1994. [PubMed: 7584044] [Full Text: https://doi.org/10.1093/dnares/1.5.223]
Okamoto, N., Ando, A., Kawai, J., Yoshiwara, T., Tsuji, K., Inoko, H. Orientation of HLA-DNA gene and identification of a CpG island-associated gene adjacent to DNA in human major histocompatibility complex class II region. Hum. Immun. 32: 221-228, 1991. [PubMed: 1663500] [Full Text: https://doi.org/10.1016/0198-8859(91)90059-i]
Thorpe, K. L., Abdulla, S., Kaufman, J., Trowsdale, J., Beck, S. Phylogeny and structure of the RING3 gene. Immunogenetics 44: 391-396, 1996. [PubMed: 8781126] [Full Text: https://doi.org/10.1007/BF02602785]
Xie, L., Dong, P., Qi, Y., Hsieh, T. S., English, B. P., Jung, S., Chen, X., De Marzio, M., Casellas, R., Chang, H. Y., Zhang, B., Tjian, R., Liu, Z. BRD2 compartmentalizes the accessible genome. Nature Genet. 54: 481-491, 2022. [PubMed: 35410381] [Full Text: https://doi.org/10.1038/s41588-022-01044-9]