BRDT
Bromodomain testis-specific protein is a protein that in humans is encoded by the BRDT gene. It is a member of the Bromodomain and Extra-terminal motif (BET) protein family.[5][6]
BRDT is similar to the RING3 protein family. It possesses 2 bromodomain motifs and a PEST sequence (a cluster of proline, glutamic acid, serine, and threonine residues), characteristic of proteins that undergo rapid intracellular degradation. The bromodomain is found in proteins that regulate transcription. Two transcript variants encoding the same protein have been found for this gene.[6]
The use of three different mouse models (Brdt knock-out mice, mice expressing a non-functional Brdt and mice expressing a mutated Brdt lacking its first bromodomain) showed that Brdt drives a meiotic and post-meiotic gene expression program. It also controls the genome-wide post-meiotic genome reorganization that occurs after histone hyperacetylation in elongating spermatids.[6][7]
Model organisms
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Normal |
| Fertility | Abnormal |
| Body weight | Normal |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Abnormal[8] |
| Body temperature | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Plasma immunoglobulins | Normal |
| Haematology | Normal |
| Micronucleus test | Normal |
| Heart weight | Normal |
| Tail epidermis wholemount | Normal |
| Skin Histopathology | Normal |
| Brain histopathology | Normal |
| Salmonella infection | Normal[9] |
| Citrobacter infection | Normal[10] |
| All tests and analysis from[11][12] |
Model organisms have been used in the study of BRDT function. A conditional knockout mouse line, called Brdttm1a(EUCOMM)Wtsi[13][14] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[15][16][17]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[11][18] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[11] Homozygous mutant males were sub-fertile and both sexes had a decreased number of lumbar and sacral vertebrae.[11]
Potential as target of male contraceptive medication
BET inhibitors such as JQ1 block the region of BRDT responsible for chromatin binding, and cause a reversible reduction of sperm production, sperm quality, and size of the testis in mice.[19] The mechanism of action of JQ1 could be explained by considering Brdt’s functions as a driver of testis-specific gene expression and post-meiotic chromatin reorganization.[6][7] As BET inhibitors also inhibit other BET proteins BRD2, BRD3, and BRD4, they are likely to have effects in people beyond temporary male sterility.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000137948 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029279 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Jones MH, Numata M, Shimane M (Jan 1998). "Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh". Genomics. 45 (3): 529–34. doi:10.1006/geno.1997.5000. PMID 9367677.
- ^ a b c d "Entrez Gene: BRDT bromodomain, testis-specific".
- ^ a b Gaucher J, Boussouar F, Montellier E, Curtet S, Buchou T, Bertrand S, Hery P, Jounier S, Depaux A, Vitte AL, Guardiola P, Pernet K, Debernardi A, Lopez F, Holota H, Imbert J, Wolgemuth DJ, Gérard M, Rousseaux S, Khochbin S (2012). "Bromodomain-dependent stage-specific male genome programming by Brdt". EMBO J. 31 (19): 3809–20. doi:10.1038/emboj.2012.233. PMC 3463845. PMID 22922464.
- ^ "Radiography data for Brdt". Wellcome Trust Sanger Institute.
- ^ "Salmonella infection data for Brdt". Wellcome Trust Sanger Institute.
- ^ "Citrobacter infection data for Brdt". Wellcome Trust Sanger Institute.
- ^ a b c d Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
- ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
- ^ "International Knockout Mouse Consortium".[permanent dead link]
- ^ "Mouse Genome Informatics".
- ^ Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
- ^ Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- ^ Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
- ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ "A male contraceptive pill in the making?". 16 August 2012. Retrieved 17 August 2012.
External links
- Human BRDT genome location and BRDT gene details page in the UCSC Genome Browser.
Further reading
- Zheng Y, Yuan W, Zhou Z, et al. (2005). "Molecular cloning and expression of a novel alternative splice variant of BRDT gene". Int. J. Mol. Med. 15 (2): 315–21. doi:10.3892/ijmm.15.2.315. PMID 15647849.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Pivot-Pajot C, Caron C, Govin J, et al. (2003). "Acetylation-Dependent Chromatin Reorganization by BRDT, a Testis-Specific Bromodomain-Containing Protein". Mol. Cell. Biol. 23 (15): 5354–65. doi:10.1128/MCB.23.15.5354-5365.2003. PMC 165724. PMID 12861021.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Hartley JL, Temple GF, Brasch MA (2001). "DNA Cloning Using In Vitro Site-Specific Recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Scanlan MJ, Altorki NK, Gure AO, et al. (2000). "Expression of cancer-testis antigens in lung cancer: definition of bromodomain testis-specific gene (BRDT) as a new CT gene, CT9". Cancer Lett. 150 (2): 155–64. doi:10.1016/S0304-3835(99)00385-7. PMID 10704737.
- Dhalluin C, Carlson JE, Zeng L, et al. (1999). "Structure and ligand of a histone acetyltransferase bromodomain". Nature. 399 (6735): 491–6. doi:10.1038/20974. PMID 10365964.