Double bromodomain‐containing gene Brd2 is essential for embryonic development in mouse
Open accessAbstract
The BET subfamily of bromodomain‐containing genes is characterized by the presence of two bromodomains and a unique ET domain at their carboxyl termini. Here, we show that the founding member of this subfamily, Brd2, is an essential gene by generating a mutant mouse line lacking Brd2 function. Homozygous Brd2 mutants are embryonic lethal, with most Brd2−/− embryos dying by embryonic day 11.5. Before death, the homozygous embryos were notably smaller and exhibited abnormalities in the neural tube where the gene is highly expressed. Brd2‐deficient embryonic fibroblast cells were observed to proliferate more slowly than controls. Experiments to explore whether placental insufficiency could be a cause of the embryonic lethality showed that injecting diploid mutant embryonic stem cells into tetraploid wild‐type blastocysts did not rescue the lethality; that is Brd2‐deficient embryos could not be rescued by wild‐type extraembryonic tissues. Furthermore, there were enhanced levels of cell death in Brd2‐deficient embryos. Developmental Dynamics 238:908–917, 2009. © 2009 Wiley‐Liss, Inc.
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Simultaneous degradation of the three BRD proteins may increase drug toxicities.
“However, simultaneous degradation of the three BRD proteins may increase drug toxicities [100–102].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [100]
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Cites
Manipulating the mouse embryo: A laboratory manual
Hogan, B. L. M., Costantini, F. D., & Lacy, E. (1986) · Cited by 4,460 · see citing works
Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.
Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W., & Roder, J. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.18.8424 · Cited by 2,328 · see citing works
Manipulating the Mouse Embryo: A Laboratory Manual
Behringer, R. R., Gertsenstein, M., Nagy, K. V., & Nagy, A. (2002) · Cited by 2,046 · see citing works
Tamkun, J. W., Deuring, R., Scott, M. P., Kissinger, M., Pattatucci, A. M. L., Kaufman, T. C., & Kennison, J. A. (1992) · Cell · doi:10.1016/0092-8674(92)90191-e · Cited by 966 · see citing works
Bromodomain: an acetyl‐lysine binding domain
Zeng, L., & Zhou, M. (2002) · FEBS Letters · doi:10.1016/s0014-5793(01)03309-9 · Cited by 751 · see citing works
Barlev, N. A., Liu, L., Chehab, N. H., Mansfield, K., Harris, K. G., Halazonetis, T. D., & Berger, S. L. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00414-2 · Cited by 710 · see citing works
You, J., Croyle, J. L., Nishimura, A., Ozato, K., & Howley, P. M. (2004) · Cell · doi:10.1016/s0092-8674(04)00402-7 · Cited by 402 · see citing works
The bromodomain: a conserved sequence found in human,Drosophilaand yeast proteins
Haynes, S. R., Dollard, C. A., Winston, F., Beck, S., Trowsdale, J., & Dawid, I. B. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.10.2603 · Cited by 387 · see citing works
The Double Bromodomain Proteins Brd2 and Brd3 Couple Histone Acetylation to Transcription
LeRoy, G., Rickards, B., & Flint, S. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.01.018 · Cited by 374 · see citing works
Selective Recognition of Acetylated Histones by Bromodomain Proteins Visualized in Living Cells
Kanno, T., Kanno, Y., Siegel, R. M., Jang, M. K., Lenardo, M. J., & Ozato, K. (2004) · Molecular Cell · doi:10.1016/s1097-2765(03)00482-9 · Cited by 363 · see citing works
Lysine acetylation and the bromodomain: a new partnership for signaling
Yang, X. (2004) · BioEssays · doi:10.1002/bies.20104 · Cited by 359 · see citing works
Woermann, F. G., Free, S. L., Koepp, M. J., Sisodiya, S. M., & Duncan, J. S. (1999) · Brain · doi:10.1093/brain/122.11.2101 · Cited by 331 · see citing works
ISOLATION AND CHARACTERIZATION OF SEX-LINKED FEMALE-STERILE MUTANTS IN DROSOPHILA MELANOGASTER
Gans, M., Audit, C., & Masson, M. (1975) · Genetics · doi:10.1093/genetics/81.4.683 · Cited by 329 · see citing works
Structural Mechanism of the Bromodomain of the Coactivator CBP in p53 Transcriptional Activation
Mujtaba, S., He, Y., Zeng, L., Yan, S. X., Plotnikova, O. V., Sachchidanand, Sánchez, R., Zeleznik‐Le, N. J., Ronai, Z. A., & Zhou, M. (2004) · Molecular Cell · doi:10.1016/s1097-2765(03)00528-8 · Cited by 318 · see citing works
Houzelstein, D., Bullock, S. L., Lynch, D. E., Grigorieva, E. F., Wilson, V. A., & Beddington, R. S. P. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.11.3794-3802.2002 · Cited by 318 · see citing works
Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6
Greenberg, D. A., Delgado‐Escueta, A. V., Widelitz, H., Sparkes, R. S., Treiman, L. J., Maldonado, H. M., Park, M. S., Terasaki, P. I., Opitz, J. M., & Reynolds, J. F. (1988) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320310125 · Cited by 305 · see citing works
Self-citationJeanmougin, F. (1997) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(97)01042-6 · Cited by 279 · see citing works
Shang, E., Nickerson, H. D., Wen, D., Wang, X., & Wolgemuth, D. J. (2007) · Development · doi:10.1242/dev.004481 · Cited by 275 · see citing works
Self-citationThe bromodomain: a chromatin-targeting module?
Winston, F., & Allis, C. D. (1999) · Nature Structural Biology · doi:10.1038/10640 · Cited by 270 · see citing works
Durner, M., Sander, T., Greenberg, D. A., et al. (1991) · Neurology · doi:10.1212/wnl.41.10.1651 · Cited by 194 · see citing works
Self-citationBRD2 (RING3) Is a Probable Major Susceptibility Gene for Common Juvenile Myoclonic Epilepsy
Pal, D. K., Evgrafov, O. V., Tabares, P., Zhang, F., Durner, M., & Greenberg, D. A. (2003) · The American Journal of Human Genetics · doi:10.1086/377006 · Cited by 189 · see citing works
Self-citationYou bet-cha a novel family of transcriptional regulators
Florence, B. (2001) · Frontiers in bioscience · doi:10.2741/florence · Cited by 178 · see citing works
PLATT, G. M., Simpson, G. R., Mittnacht, S., et al. (1999) · Journal of Virology · doi:10.1128/jvi.73.12.9789-9795.1999 · Cited by 165 · see citing works
RING3 kinase transactivates promoters of cell cycle regulatory genes through E2F.
Denis, G. V., Vaziri, C., Guo, N., et al. (2000) · PubMed · Cited by 158 · see citing works
Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6
Weissbecker, K., Durner, M., Janz, D., et al. (1991) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320380109 · Cited by 154 · see citing works
Denis, G. V., McComb, M. E., Faller, D. V., Sinha, A., Romesser, P. B., & Costello, C. E. (2006) · Journal of Proteome Research · doi:10.1021/pr050430u · Cited by 144 · see citing works
An, F., Compitello, N., Horwitz, E., Sramkoski, M., Knudsen, E., & Renne, R. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m407435200 · Cited by 140 · see citing works
Legan, P. K., Collins, J. E., & Garrod, D. R. (2006) · BioEssays · doi:10.1002/(issn)1521-1878 · Cited by 131 · see citing works
Shang, E., Salazar, G., Crowley, T. E., et al. (2004) · Gene Expression Patterns · doi:10.1016/j.modgep.2004.03.002 · Cited by 126 · see citing works
Self-citationA novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulator.Preprint
Denis, G. V., & Green, M. R. (1996) · Genes & Development · doi:10.1101/gad.10.3.261 · Cited by 124 · see citing works
Genetic and molecular analysis of fs(1)h, a maternal effect homeotic gene in Drosophila
Digan, M. E., Haynes, S. R., Mozer, B. A., et al. (1986) · Developmental Biology · doi:10.1016/0012-1606(86)90392-1 · Cited by 122 · see citing works
Greenberg, D. A., Durner, M., Keddache, M. A., et al. (2000) · The American Journal of Human Genetics · doi:10.1086/302763 · Cited by 121 · see citing works
Self-citationCrystal Structure of the Human BRD2 Bromodomain
Nakamura, Y., Umehara, T., Nakano, K., Jang, M. K., Shirouzu, M., Morita, S., Uda‐Tochio, H., Hamana, H., Terada, T., Adachi, N., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605971200 · Cited by 120 · see citing works
Viejo‐Borbolla, A., Ottinger, M., Brüning, E., Bürger, A., König, R., Kati, E., Sheldon, J., & Schulz, T. F. (2005) · Journal of Virology · doi:10.1128/jvi.79.21.13618-13629.2005 · Cited by 120 · see citing works
Eμ-BRD2 transgenic mice develop B-cell lymphoma and leukemia
Greenwald, R. J., Tumang, J. R., Sinha, A., Currier, N. V., Cardiff, R. D., Rothstein, T. L., Faller, D. V., & Denis, G. V. (2003) · Blood · doi:10.1182/blood-2003-06-2116 · Cited by 109 · see citing works
Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A
Sinha, A., Faller, D. V., & Denis, G. V. (2005) · Biochemical Journal · doi:10.1042/bj20041793 · Cited by 105 · see citing works
Increased Affinity of c-Myb for CREB-binding Protein (CBP) after CBP-induced Acetylation
Sano, Y., & Ishii, S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006896200 · Cited by 102 · see citing works
Interaction between Acetylated MyoD and the Bromodomain of CBP and/or p300
Polesskaya, A., Naguibneva, I., Duquet, A., Bengal, E., Robin, P., & Harel‐Bellan, A. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.16.5312-5320.2001 · Cited by 100 · see citing works
Genetic dissection of photosensitivity and its relation to idiopathic generalized epilepsy
Tauer, U., Lorenz, S., Lenzen, K. P., et al. (2005) · Annals of Neurology · doi:10.1002/ana.20500 · Cited by 93 · see citing works
Development and Therapeutic Potential of Calpain Inhibitors
Wang, K., & Yuen, P. (1996) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60949-7 · Cited by 90 · see citing works
Jacob, A. L. J., Lund, J., Martı́nez, P., & Hedin, L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104427200 · Cited by 90 · see citing works
Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6
Sander, T., Bockenkamp, B., Hildmann, T., et al. (1997) · Neurology · doi:10.1212/wnl.49.3.842 · Cited by 90 · see citing works
An Efficient Method for the Derivation of Mouse Embryonic Stem Cells
Bryja, V., Bonilla, S., Čajánek, L., Parish, C. L., Schwartz, C. M., Luo, Y., Rao, M. S., & Arenas, E. (2005) · Stem Cells · doi:10.1634/stemcells.2005-0444 · Cited by 89 · see citing works
Beck, S., Hanson, I. M., Kelly, A. P., Pappin, D., & Trowsdale, J. (1992) · DNA sequence · doi:10.3109/10425179209020804 · Cited by 86 · see citing works
The Drosophila fsh locus, a maternal effect homeotic gene, encodes apparent membrane proteins
Haynes, S. R., Mozer, B. A., Bhatia‐Dey, N., & Dawid, I. B. (1989) · Developmental Biology · doi:10.1016/0012-1606(89)90094-8 · Cited by 84 · see citing works
Mouse phenotypes: a handbook of mutation analysis.
Papaioannou, V. E., & Behringer, R. R. (2005) · Medical Entomology and Zoology · Cited by 68 · see citing works
Tae, W., Hong, S. B., Joo, E. Y., et al. (2006) · Korean Journal of Radiology · doi:10.3348/kjr.2006.7.3.162 · Cited by 68 · see citing works
Hindbrain and Cranial Nerve Dysmorphogenesis Result from Acute Maternal Ethanol Administration
Dunty, W. C., Zucker, R. M., & Sulik, K. K. (2002) · Developmental Neuroscience · doi:10.1159/000066748 · Cited by 66 · see citing works
A Multicenter Study of BRD2 as a Risk Factor for Juvenile Myoclonic Epilepsy
Cavalleri, G. L., Walley, N. M., Soranzo, N., Mulley, J. C., Doherty, C. P., Kapoor, A., Depondt, C., Lynch, J. M., Scheffer, I. E., Heils, A., et al. (2007) · Epilepsia · doi:10.1111/j.1528-1167.2007.00977.x · Cited by 63 · see citing works
Huang, H., Zhang, J., Shen, W., Wang, X., Wu, J., Wu, J., & Shi, Y. (2007) · BMC Structural Biology · doi:10.1186/1472-6807-7-57 · Cited by 62 · see citing works
Self-citationMattsson, K., Kiss, C., Platt, G., Simpson, G. R., Kashuba, E., Klein, G., Schulz, T. F., & Székely, L. (2002) · Journal of General Virology · doi:10.1099/0022-1317-83-1-179 · Cited by 61 · see citing works
Association of BRD2 polymorphisms with photoparoxysmal response
Lorenz, S., Taylor, K. P., Gehrmann, A., et al. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.02.026 · Cited by 59 · see citing works
Activation-induced nuclear translocation of RING3
Guo, N., Faller, D. V., & Denis, G. V. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.17.3085 · Cited by 59 · see citing works
Epidemiology and Genetics of Epilepsy
Annegers, J. F. (1994) · Neurologic Clinics · doi:10.1016/s0733-8619(18)30108-7 · Cited by 59 · see citing works
Rhee, K., Brunori, M., Besset, V., et al. (1998) · Journal of Cell Science · doi:10.1242/jcs.111.23.3541 · Cited by 50 · see citing works
Chang, Y.-L., King, B. O., Lin, S., Kennison, J. A., & Huang, D.-H. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00692-07 · Cited by 46 · see citing works
A Genetic Screen of the Drosophila X Chromosome for Mutations That Modify Deformed Function
Florence, B., & McGinnis, W. J. (1998) · Genetics · doi:10.1093/genetics/150.4.1497 · Cited by 43 · see citing works
Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy
Pal, D. K., Durner, M., Klotz, I., Dicker, E., Shinnar, S., Resor, S. R., Cohen, J., Harden, C. L., Moshé, S. L., Ballaban‐Gil, K. R., et al. (2006) · Brain and Development · doi:10.1016/j.braindev.2005.05.009 · Cited by 43 · see citing works
Self-citationGans, M., Forquignon, F., & Masson, M. (1980) · Genetics · doi:10.1093/genetics/96.4.887 · Cited by 42 · see citing works
Phylogeny and structure of theRING3 gene
Thorpe, K. L., Abdulla, S., Kaufman, J., et al. (1996) · Immunogenetics · doi:10.1007/bf02602785 · Cited by 39 · see citing works
Wang, S., DiBenedetto, A. J., & Pittman, R. N. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8655 · Cited by 39 · see citing works
Lenburg, M. E., Sinha, A., Faller, D. V., & Denis, G. V. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605870200 · Cited by 36 · see citing works
Crowley, T. E., Brunori, M., Rhee, K., Wang, X., & Wolgemuth, D. J. (2004) · Developmental Brain Research · doi:10.1016/j.devbrainres.2003.12.011 · Cited by 31 · see citing works
Self-citationTrousdale, R. K., & Wolgemuth, D. J. (2004) · Molecular Reproduction and Development · doi:10.1002/mrd.20059 · Cited by 30 · see citing works
Self-citationDiBenedetto, A. J., Guinto, J. B., Ebert, T., Bee, K. J., Schmidt, M. M., & Jackman, T. R. (2008) · BMC Developmental Biology · doi:10.1186/1471-213x-8-39 · Cited by 24 · see citing works
Florence, B., & Faller, D. V. (2008) · Developmental Dynamics · doi:10.1002/dvdy.21432 · Cited by 22 · see citing works
BelAiba, R. S., Baril, P., Chebloune, Y., et al. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02355.x · Cited by 8 · see citing works
Umehara, T., Wakamori, M., Tanaka, A., et al. (2007) · Acta Crystallographica Section F Structural Biology and Crystallization Communications · doi:10.1107/s1744309107028473 · Cited by 3 · see citing works
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- Authors
- Shang, E., Wang, X., Wen, D., Greenberg, D. A., & Wolgemuth, D. J.
- Affiliations
- Columbia University Irving Medical Center (US)
- Rockefeller University (US)
- Corresponding author
- Wolgemuth, Debra J.
- Venue
- Developmental Dynamics
- Publisher
- Wiley
- Published
- 2009-03-19
- Volume
- 238
- Issue
- 4
- Pages
- 908-917
- ISSN
- 1058-8388 (ISSN-L)
- 1097-0177
- PMC
- PMC2771124
- OpenAlex
- W1983619854
- Cited by
- 156
- References
- 68
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 6 · 2023: 5 · 2022: 13 · 2021: 10 · 2020: 11 · 2019: 12 · 2018: 8 · 2017: 10 · 2016: 14 · 2015: 10 · 2014: 13 · 2013: 8 · 2012: 9
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Developmental Dynamics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM081767, GM081767)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-31775, R01DK031775, T32 DK07647, T32DK007647)
- National Institute of Neurological Disorders and Stroke (R01NS027941, NS-27941)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- BRD2, BET proteins, embryonic lethality, neural tube defects, placental insufficiency, cell proliferation, cell death, extraembryonic tissues, gene essentiality
- MeSH terms
- Bromodomain Containing Proteins, Animals, Brain, Cell Line, Chromosomal Proteins, Non-Histone, Embryo, Mammalian, Female, Fibroblasts, Mutation, Phenotype, Placenta, Transcription Factors, Cell Death, Protein Serine-Threonine Kinases, Mice, Knockout, Gene Expression Regulation, Developmental, Embryo Loss, Cell Proliferation, Mice
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