Affinage

BRDT

Bromodomain testis-specific protein · UniProt Q58F21

Length
947 aa
Mass
108.0 kDa
Annotated
2026-06-09
38 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRDT is a testis-specific BET-family double-bromodomain protein that serves as a master epigenetic regulator of meiotic and post-meiotic gene expression and chromatin remodeling during spermatogenesis (PMID:22922464). Its first bromodomain (BD1) recognizes hyperacetylated histone H4 in an acetylation-dependent manner and drives large-scale, ATP-independent chromatin reorganization (PMID:12861021); BD1-mediated acetyl-lysine recognition is complemented by a direct bromodomain–DNA contact that enhances nucleosome binding affinity, specificity, and localization to acetylated chromatin (PMID:27991587). Through BD1 this activity directs the genome-wide replacement of histones by transition proteins during the global hyperacetylation of post-meiotic spermatids (PMID:22922464), and BD1 is required in vivo for spermatid morphogenesis, peri-nuclear heterochromatin foci, and chromocenter integrity (PMID:17728347, PMID:22020252). BRDT also assembles into repressive complexes with HDAC1, PRMT5, and TRIM28 that occupy the H1t promoter, with BD1 loss derepressing H1t (PMID:26565999, PMID:17728347), and it partners with spliceosome components (Srsf2, Ddx5, Hnrnpk, Tardbp) to control mRNA splicing and 3'-UTR truncation in round spermatids (PMID:22570411). In meiosis BRDT cooperates with A-MYB to release paused RNA Pol II in a coordinated transcriptional burst at meiotic genes (PMID:36990976) and is required for meiotic sex chromosome inactivation, synapsis, and crossover homeostasis (PMID:29513658). BRDT protein stability is controlled by PHF7, an E3 ligase for histone H3K14 that attenuates BRDT ubiquitination to enable histone-to-protamine exchange (PMID:32726616). The acetyl-lysine pocket is druggable: JQ1 occupies it and produces a reversible contraceptive effect in mice (PMID:22901802), establishing BRDT as a male contraceptive target. Beyond spermatogenesis, BRDT has been implicated in cancer contexts including ΔNp63-driven super-enhancer transcription in esophageal squamous cell carcinoma and c-myc/eIF4EBP1 regulation in renal cell carcinoma (PMID:33658703, PMID:33125143).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 High

    Established the core biochemical activity of BRDT—recognition of hyperacetylated H4 and induction of chromatin compaction—answering whether BRDT reads acetyl marks and reorganizes chromatin.

    Evidence In vitro chromatin remodeling on isolated nuclei with bromodomain mutagenesis and ectopic expression in TSA-treated somatic cells

    PMID:12861021

    Open questions at the time
    • Did not establish the in vivo germ-cell substrate or downstream effectors
    • ATP-independent mechanism of compaction not resolved structurally
  2. 2007 High

    Demonstrated that BD1 is genetically essential for spermatid differentiation in vivo and that BRDT occupies a specific target promoter (H1t), linking the biochemical reader function to fertility.

    Evidence BD1-deletion mouse, ChIP, qRT-PCR, immunostaining

    PMID:17728347

    Open questions at the time
    • Did not define the full repertoire of BRDT-bound promoters
    • Mechanism of H1t repression not yet defined
  3. 2011 Medium

    Resolved BD1's structural role in spermatid nuclear architecture, showing BD1 is required for chromocenter integrity and spatial exclusion of HP1α and Sirt1.

    Evidence BD1-deletion mouse with immunofluorescence and colocalization analysis

    PMID:22020252

    Open questions at the time
    • Single lab, descriptive localization
    • Causal link between chromocenter defect and infertility not dissected
  4. 2012 High

    Partitioned BRDT function across spermatogenic stages, establishing it as a master regulator that uses BD1 for post-meiotic histone replacement and other domains for meiotic transcription, and identified its physical partners.

    Evidence Brdt knockout and BD1-deletion mice with genome-wide transcriptional/ChIP analysis; co-IP with Smarce1 and with spliceosome components (Srsf2, Ddx5, Hnrnpk, Tardbp); JQ1 crystal structure with in vivo contraception

    PMID:22215678 PMID:22570411 PMID:22901802 PMID:22922464

    Open questions at the time
    • Mechanism by which BD1 directs transition-protein exchange not biochemically reconstituted
    • Splicing/3'-UTR control mechanism not resolved at single-gene level
  5. 2015 Medium

    Defined BRDT's repressive complex composition, showing it assembles with HDAC1, PRMT5, and TRIM28 at the H1t promoter to enforce gene silencing.

    Evidence FLAG-BRDT affinity purification, co-IP from testicular extracts, ChIP, immunofluorescence

    PMID:26565999

    Open questions at the time
    • Stoichiometry and assembly order of the complex unknown
    • Single lab; complex not structurally characterized
  6. 2016 High

    Explained how BRDT achieves chromatin specificity, showing BD1 recognition of acetyl-lysine is complemented by a bromodomain–DNA interaction that enhances nucleosome binding.

    Evidence NMR, biochemical binding with site-specifically acetylated nucleosomes, cell-based localization

    PMID:27991587

    Open questions at the time
    • DNA-binding contribution to in vivo histone replacement not genetically tested
    • BD2 functional role left undefined
  7. 2018 High

    Extended BRDT function to meiotic chromosome biology, establishing it as essential for meiotic sex chromosome inactivation, synapsis, and crossover homeostasis.

    Evidence Complete Brdt knockout mouse, immunofluorescence, ChIP, FISH, meiotic progression analysis

    PMID:29513658

    Open questions at the time
    • Molecular targets mediating MSCI and crossover control not identified
    • Direct chromatin mechanism at the synaptonemal complex unresolved
  8. 2020 High

    Identified an upstream regulator of BRDT stability, showing PHF7-mediated H3K14 ubiquitination attenuates BRDT ubiquitination to permit histone-to-protamine exchange.

    Evidence Phf7-null and Phf7 C160A catalytic-mutant knockin mice, in vitro ubiquitination assay, co-IP

    PMID:32726616

    Open questions at the time
    • The E3 ligase ubiquitinating BRDT not identified
    • How H3K14ub mechanistically shields BRDT from degradation unknown
  9. 2023 Medium

    Placed BRDT in the meiotic transcriptional-burst pathway, showing it acts with A-MYB to release paused Pol II at meiotic genes.

    Evidence ATAC-seq, GRO-seq, and processed-mRNA profiling in staged spermatocytes

    PMID:36990976

    Open questions at the time
    • Direct biochemical coupling of BRDT to P-TEFb/pause-release machinery not shown
    • Single lab
  10. 2021 Medium

    Showed BRDT can be co-opted in cancer, acting at ΔNp63 super-enhancers in ESCC and regulating c-myc/eIF4EBP1 in renal cell carcinoma, while advancing selective chemical tools.

    Evidence ChIP-seq, chromatin interaction studies, co-IP/MS, knockdown and rescue in tumor cells; selective BRDT-BD2 inhibitor co-crystal structures

    PMID:33125143 PMID:33637650 PMID:33658703

    Open questions at the time
    • Physiological relevance of somatic BRDT expression unclear
    • Direct vs indirect c-myc regulation not fully separated
  11. 2022 High

    Demonstrated BRDT conformational plasticity exploitable for selectivity, with bivalent inhibitors inducing unique dimeric states distinct from BRD4.

    Evidence X-ray crystallography, solution biophysics, cell-based assays, SAR

    PMID:35867655

    Open questions at the time
    • Functional consequence of induced BRDT dimerization in cells unknown
    • Relevance to native BRDT oligomeric state not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BRDT mechanistically converts acetyl-histone recognition into directed transition-protein/protamine exchange, and how its meiotic and post-meiotic roles are temporally switched, remains unresolved.
  • No reconstituted system couples BD1 reading to histone-to-protamine exchange
  • Domain-level switch between meiotic transcription and post-meiotic remodeling undefined
  • Direct enzymatic partners executing chromatin reorganization unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 4 GO:0140110 transcription regulator activity 4 GO:0008092 cytoskeletal protein binding 2 GO:0003677 DNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 1
Partners
DDX5HDAC1HNRNPKPHF7PRMT5SMARCE1SRSF2TRIM28
Complex memberships
BRDT-HDAC1-PRMT5-TRIM28 repressive complexBRDT-spliceosome complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 BRDT specifically binds hyperacetylated histone H4 tail in an acetylation-dependent manner requiring the integrity of both bromodomains, and induces large-scale chromatin reorganization in an ATP-independent manner in somatic cells only after induction of histone hyperacetylation; both bromodomains and flanking regions are indispensable for this remodelling activity. In vitro chromatin remodeling assay on isolated nuclei, bromodomain mutagenesis, ectopic expression in somatic cells with TSA treatment Molecular and cellular biology High 12861021
2007 The first bromodomain (BD1) of Brdt is essential for male germ cell differentiation in vivo; mice lacking only BD1 are sterile with aberrant spermatid morphogenesis and lack peri-nuclear heterochromatin foci. Brdt protein (but not BrdtΔBD1) associates with the promoter of histone H1t, and BD1 deletion leads to 3-fold increased H1t levels. Targeted mutagenesis (deletion of BD1 in mice), chromatin immunoprecipitation (ChIP), quantitative RT-PCR, immunostaining Development (Cambridge, England) High 17728347
2012 JQ1, a small-molecule inhibitor, occupies the BRDT acetyl-lysine binding pocket and prevents recognition of acetylated histone H4, as confirmed by crystallography. In mice, JQ1 reduces seminiferous tubule area, testis size, and spermatozoa number and motility, causing a complete and reversible contraceptive effect at the spermatocyte and round spermatid stages. Biochemical binding assay, X-ray crystallography of JQ1-BRDT complex, in vivo mouse treatment Cell High 22901802
2012 Brdt acts as a master regulator of meiotic and post-meiotic gene expression programs; its first bromodomain directs genome-wide replacement of histones by transition proteins during global chromatin hyperacetylation at post-meiotic stages, while other domains drive a spermatogenic transcriptional program at meiotic stages. Genetic mouse models (Brdt knockout and BD1 deletion), genome-wide transcriptional analysis, ChIP, immunostaining The EMBO journal High 22922464
2012 Brdt colocalizes with acetylated H4 in elongating spermatids and induces acetylation-dependent but ATP-independent chromatin reorganization in round spermatids. Brdt interacts with Smarce1 (a SWI/SNF family member) via its N-terminus, and this interaction increases upon histone hyperacetylation both in vitro and in vivo. Immunocytochemistry, in vitro chromatin remodeling assay, co-immunoprecipitation, pulldown assay The Journal of biological chemistry Medium 22215678
2012 BRDT forms a complex with multiple spliceosome components (Srsf2, Ddx5, Hnrnpk, Tardbp) and is required for mRNA splicing and 3'-UTR truncation in round spermatids. Loss of BD1 leads to longer 3'-UTRs and reduced protein levels of splicing factors, and BD1 is essential for these functions. Transcriptome analysis of Brdt(ΔBD1/ΔBD1) vs control round spermatids, co-immunoprecipitation of BRDT with spliceosome components, RNA-seq Nucleic acids research High 22570411
2015 BRDT forms complexes with HDAC1, PRMT5, and TRIM28 in round spermatids, as shown by affinity purification of FLAG-tagged BRDT and co-IP from testicular extracts. These complexes bind the H1t promoter, and this binding is lost in Brdt(ΔBD1) mutants, correlating with elevated H1t expression, indicating a role for BRDT-containing complexes in transcriptional repression. Affinity purification of FLAG-tagged BRDT, co-immunoprecipitation from testicular extracts, ChIP, immunofluorescence Journal of cellular biochemistry Medium 26565999
2016 BRDT interacts with nucleosomes through its first bromodomain (BD1) but not second bromodomain (BD2); acetylated histone recognition by BD1 is complemented by a bromodomain-DNA interaction, which together enhance BRDT's nucleosome binding affinity, specificity, and localization to acetylated chromatin in cells. Conservation of DNA binding in BRD2, BRD3, and BRD4 bromodomains suggests this is a shared BET mechanism. NMR, biochemical nucleosome binding assay with site-specifically acetylated nucleosomes, cell-based chromatin localization assay Nature communications High 27991587
2018 Complete loss of BRDT disrupts meiotic sex chromosome inactivation in spermatocytes, affects synapsis and silencing of the X and Y chromosomes, disrupts global chromatin organization and histone modifications at the synaptonemal complex, and alters the homeostasis of crossover formation and localization during pachynema, establishing BRDT as an essential regulator of meiotic chromatin organization. Complete Brdt knockout mouse model, immunofluorescence, ChIP, FISH, analysis of meiotic progression PLoS genetics High 29513658
2020 PHF7 acts as an E3 ubiquitin ligase for histone H3K14 in post-meiotic spermatids, and its ubiquitin ligase activity stabilizes BRDT by attenuating ubiquitination of BRDT itself, thereby enabling histone-to-protamine exchange. Loss of PHF7 E3 ligase activity leads to dysregulation of BRDT in early condensing spermatids and defects in histone-to-protamine exchange. Phf7-deficient mice, Phf7 C160A knockin mice (impaired E3 ligase), biochemical ubiquitination assay, co-immunoprecipitation Cell reports High 32726616
2011 The first bromodomain of Brdt is required for chromocenter integrity in spermatids; Brdt(ΔBD1/ΔBD1) mutants exhibit fragmented chromocenters with increased HP1α levels and ectopic H1fnt localization. Brdt protein is normally excluded from the chromocenter and appears to separate Sirt1 from contact with the chromocenter, a spatial relationship lost upon BD1 deletion. Brdt(ΔBD1/ΔBD1) mouse model, immunofluorescence microscopy, co-localization analysis Developmental biology Medium 22020252
2021 In esophageal squamous cell carcinoma (ESCC), BRDT colocalizes and interacts with ΔNp63 at super-enhancers to drive transcriptional activation of ΔNp63 target genes (including KRT14, FAT2, PTHLH) that are involved in squamous cell identity; BRDT promotes cell migration but is dispensable for proliferation in this context. BET PROTAC MZ1 preferentially degrades BRDT over BRD2, BRD3, and BRD4. ChIP-seq, genome-wide chromatin interaction studies, transcriptome analysis, co-immunoprecipitation, CRISPR/shRNA knockdown Cell death and differentiation Medium 33658703
2021 CDD-1102 is a selective BRDT-BD2 inhibitor with low nanomolar potency and >1,000-fold selectivity over BRDT-BD1. Co-crystal structures of BRDT-BD2 with CDD-1102 and CDD-1302 (at 2.27 and 1.90 Å resolution) reveal BRDT-BD2-specific contacts explaining their affinity and selectivity. DNA-encoded chemical library screening, AlphaScreen competition assay, X-ray crystallography of BRDT-BD2 inhibitor complexes, BROMOscan profiling Proceedings of the National Academy of Sciences of the United States of America High 33637650
2020 In renal cell carcinoma cells, BRDT interacts with eIF4EBP1 (identified by immunoprecipitation and mass spectrometry), and BRDT inhibition or knockdown suppresses eIF4EBP1 protein expression and c-myc transcription; BRDT regulates c-myc promoter activity, and eIF4EBP1 overexpression partially rescues the growth inhibition caused by BRDT inhibition. Co-immunoprecipitation, mass spectrometry, siRNA knockdown, luciferase reporter assay, in vivo xenograft Oncology reports Medium 33125143
2017 A homozygous BRDT mutation (p.G928D) in the P-TEFb binding domain causes acephalic spermatozoa and mis-regulation of 899 genes compared to wild-type BRDT-expressing cells, with upregulated genes enriched in intracellular transport, RNA splicing, cell cycle, and DNA metabolic processes. Whole-exome sequencing, RNA-sequencing of mutant vs wild-type cells, Gene Ontology analysis Oncotarget Low 28199965
2023 During meiotic prophase I, RNA Pol II is loaded and maintained in a paused state early during prophase I; in later stages, paused Pol II is released in a coordinated transcriptional burst mediated by both A-MYB and BRDT, resulting in approximately 3-fold increase in transcription at genes required for meiotic progression. Genome-wide chromatin accessibility (ATAC-seq), nascent transcription measurement (GRO-seq), processed mRNA profiling in staged spermatocytes Nature communications Medium 36990976
2022 Bivalent BET inhibitors show increased potency and selectivity for BRDT over BRD4; X-ray crystallography and solution studies reveal that bivalent inhibitors induce unique dimeric structural states of BRDT that differ from those of BRD4, explaining the differential selectivity through protein conformational plasticity. X-ray crystallography, biophysical solution studies, cell-based activity assays, structure-activity relationship analysis Journal of medicinal chemistry High 35867655

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Small-molecule inhibition of BRDT for male contraception. Cell 325 22901802
2003 Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein. Molecular and cellular biology 224 12861021
2007 The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation. Development (Cambridge, England) 213 17728347
2012 Bromodomain-dependent stage-specific male genome programming by Brdt. The EMBO journal 205 22922464
2000 Expression of cancer-testis antigens in lung cancer: definition of bromodomain testis-specific gene (BRDT) as a new CT gene, CT9. Cancer letters 111 10704737
2016 A bromodomain-DNA interaction facilitates acetylation-dependent bivalent nucleosome recognition by the BET protein BRDT. Nature communications 102 27991587
2004 Identification of unique, differentiation stage-specific patterns of expression of the bromodomain-containing genes Brd2, Brd3, Brd4, and Brdt in the mouse testis. Gene expression patterns : GEP 99 15261828
1997 Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh. Genomics 99 9367677
2017 Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa. Oncotarget 71 28199965
2021 Discovery and characterization of bromodomain 2-specific inhibitors of BRDT. Proceedings of the National Academy of Sciences of the United States of America 57 33637650
2012 Insights into role of bromodomain, testis-specific (Brdt) in acetylated histone H4-dependent chromatin remodeling in mammalian spermiogenesis. The Journal of biological chemistry 56 22215678
2011 The first bromodomain of the testis-specific double bromodomain protein Brdt is required for chromocenter organization that is modulated by genetic background. Developmental biology 56 22020252
2018 BRDT is an essential epigenetic regulator for proper chromatin organization, silencing of sex chromosomes and crossover formation in male meiosis. PLoS genetics 51 29513658
2012 The testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3'-UTR truncation in round spermatids. Nucleic acids research 41 22570411
2020 PHF7 Modulates BRDT Stability and Histone-to-Protamine Exchange during Spermiogenesis. Cell reports 37 32726616
2011 Association study of single-nucleotide polymorphisms in FASLG, JMJDIA, LOC203413, TEX15, BRDT, OR2W3, INSR, and TAS2R38 genes with male infertility. Journal of andrology 37 22016351
2023 A-MYB and BRDT-dependent RNA Polymerase II pause release orchestrates transcriptional regulation in mammalian meiosis. Nature communications 31 36990976
2015 BET Protein BRDT Complexes With HDAC1, PRMT5, and TRIM28 and Functions in Transcriptional Repression During Spermatogenesis. Journal of cellular biochemistry 26 26565999
2010 The interaction of modified histones with the bromodomain testis-specific (BRDT) gene and its mRNA level in sperm of fertile donors and subfertile men. Reproduction (Cambridge, England) 26 20538714
2021 Bromodomain protein BRDT directs ΔNp63 function and super-enhancer activity in a subset of esophageal squamous cell carcinomas. Cell death and differentiation 25 33658703
2017 The Role of Bromodomain Testis-Specific Factor, BRDT, in Cancer: A Biomarker and A Possible Therapeutic Target. Cell journal 18 28580303
2020 BRDT is a novel regulator of eIF4EBP1 in renal cell carcinoma. Oncology reports 17 33125143
2020 BRDT promotes ovarian cancer cell growth. Cell death & disease 16 33257688
2022 Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity. Journal of medicinal chemistry 14 35867655
2005 Molecular cloning and expression of a novel alternative splice variant of BRDT gene. International journal of molecular medicine 10 15647849
2016 The Bromodomain testis-specific gene (Brdt) characterization and expression in gilthead seabream, Sparus aurata, and European seabass, Dicentrarchus labrax. European journal of histochemistry : EJH 9 27349318
2014 BRDT gene sequence in human testicular pathologies and the implication of its single nucleotide polymorphism (rs3088232) on fertility. Andrology 8 24865796
2012 Low-hanging fruit: targeting Brdt in the testes. The EMBO journal 8 22960636
2015 Two bromodomain proteins functionally interact to recapitulate an essential BRDT-like function in Drosophila spermatocytes. Open biology 7 25652540
2023 Novel indenopyrrol-4-one derivatives as potent BRDT inhibitors: synthesis, molecular docking, drug-likeness, ADMET, and DFT studies. Journal of biomolecular structure & dynamics 6 37528682
2016 New insights into the role of the Brdt protein in the regulation of development and spermatogenesis in the mouse. Gene expression patterns : GEP 6 26994494
2014 Genetic association study of RNF8 and BRDT variants with non-obstructive azoospermia in the Chinese Han population. Systems biology in reproductive medicine 6 25374327
2015 Brdt Bromodomains Inhibitors and Other Modern Means of Male Contraception. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 5 26469117
2016 Identification of novel potent human testis-specific and bromodomain-containing protein (BRDT) inhibitors using crystal structure-based virtual screening. International journal of molecular medicine 4 27220398
2022 The novel BRDT inhibitor NHWD870 shows potential as a male contraceptive in mice. Acta biochimica et biophysica Sinica 3 36239350
2022 Epigenetic Dysregulation of BRDT Gene in Testis Tissues of Infertile Men: Case-Control Study. Cell journal 2 35279966
2026 Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors. Journal of medicinal chemistry 0 41984625
2012 [Preparation of anti-BRDT-NY polyclonal antibody and expression of BRDT-NY protein in digestive tract tumors]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 22863594

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