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Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [ChIP-seq]

ABSTRACT: Using an unbiased method, we found a testis-specific epigenetic reader protein BRDT to be expressed and functional active in a significant portion of ESCC patients. Mechanistically, BRDT co-localizes with ΔNp63, a defining transcription factor for squamous subtype, at selected super-enhancers to regulate ΔNp63-dependent transcription programs to promote cell migration. Pharmacologically depleting BRDT resembles the effects of knock-down of BRDT, thus providing a promising clinical approach for precision medicine in a subset of ESCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155183 | GEO | 2021/03/05

REPOSITORIES: GEO

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Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [HiChIP]

Project description:Using an unbiased method, we found a testis-specific epigenetic reader protein BRDT to be expressed and functional active in a significant portion of ESCC patients. Mechanistically, BRDT co-localizes with ΔNp63, a defining transcription factor for squamous subtype, at selected super-enhancers to regulate ΔNp63-dependent transcription programs to promote cell migration. Pharmacologically depleting BRDT resembles the effects of knock-down of BRDT, thus providing a promising clinical approach for precision medicine in a subset of ESCC.

2021-03-05 | GSE155184 | GEO

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [RNA-seq]

2021-03-05 | GSE155186 | GEO

Bromodomain protein BRDT directs ΔNp63 function and super-enhancer activity in a subset of esophageal squamous cell carcinomas.

Project description:Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer with a particularly high prevalence in certain geographical regions and a poor prognosis with a 5-year survival rate of 15-25%. Despite numerous studies characterizing the genetic and transcriptomic landscape of ESCC, there are currently no effective targeted therapies. In this study, we used an unbiased screening approach to uncover novel molecular precision oncology targets for ESCC and identified the bromodomain and extraterminal (BET) family member bromodomain testis-specific protein (BRDT) to be uniquely expressed in a subgroup of ESCC. Experimental studies revealed that BRDT expression promotes migration but is dispensable for cell proliferation. Further mechanistic insight was gained through transcriptome analyses, which revealed that BRDT controls the expression of a subset of ΔNp63 target genes. Epigenome and genome-wide occupancy studies, combined with genome-wide chromatin interaction studies, revealed that BRDT colocalizes and interacts with ΔNp63 to drive a unique transcriptional program and modulate cell phenotype. Our data demonstrate that these genomic regions are enriched for super-enhancers that loop to critical ΔNp63 target genes related to the squamous phenotype such as KRT14, FAT2, and PTHLH. Interestingly, BET proteolysis-targeting chimera, MZ1, reversed the activation of these genes. Importantly, we observed a preferential degradation of BRDT by MZ1 compared with BRD2, BRD3, and BRD4. Taken together, these findings reveal a previously unknown function of BRDT in ESCC and provide a proof-of-concept that BRDT may represent a novel therapeutic target in cancer.

| S-EPMC8257622 | biostudies-literature

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas

Project description:Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas

| PRJNA648936 | ENA

Bromodomain-dependent stage-specific male genome programming by Brdt

Project description:This SuperSeries is composed of the following subset Series: GSE39908: Bromodomain-dependent stage-specific male genome programming by Brdt [ChIP-Seq] GSE39909: Bromodomain-dependent stage-specific male genome programming by Brdt [Illumina BeadArray] Refer to individual Series

2012-08-30 | E-GEOD-39910 | biostudies-arrayexpress

Bromodomain-dependent stage-specific male genome programming by Brdt [Illumina BeadArray]

Project description:Male germ cell differentiation is a highly regulated multistep process initiated by the commitment of progenitor cells into meiosis and characterized by major chromatin reorganizations in haploid spermatids. We report here that a single member of the double bromodomain BET factors, Brdt, is a master regulator of both meiotic divisions and post-meiotic genome repackaging. Upon its activation at the onset of meiosis, Brdt drives and determines the developmental timing of a testis-specific gene expression program. In meiotic cells, Brdt initiates a genuine histone acetylation-guided programming of the genome by activating essential meiotic genes and repressing a “progenitor cells” gene expression program, while “priming” a post-meiotic gene group for further activation. At post-meiotic stages, a global chromatin hyperacetylation gives the signal for Brdt’s first bromodomain to direct the genome-wide replacement of histones by transition proteins. Brdt is therefore a unique and essential regulator of male germ cell differentiation, which, by using various domains in a developmentally controlled manner, first drives a specific spermatogenic gene expression program, and later controls the tight packaging of the male genome. Total RNA obtained from testes from prepuberal mice at 17dpp and at 20dpp were compared between Brdt-/- and Brdt+/- (17dpp), between Brdt-/- and Brdt +/+ (20dpp) and between BrdtBD1del and Brdt wt mice (20dpp). In each experiments, 6 replicates of each genotype and condition were used.

2012-08-30 | E-GEOD-39909 | biostudies-arrayexpress

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [HiChIP]

Project description:Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [HiChIP]

| PRJNA648935 | ENA

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [ChIP-seq]

Project description:Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [ChIP-seq]

| PRJNA648933 | ENA

Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [RNA-seq]

Project description:Bromodomain testis-specific protein BRDT directs ΔNp63 function and super enhancer activity in a distinct subset of esophageal squamous cell carcinomas [RNA-seq]

| PRJNA648938 | ENA

Bromodomain-dependent stage-specific male genome programming by Brdt [ChIP-Seq]

Project description:Male germ cell differentiation is a highly regulated multistep process initiated by the commitment of progenitor cells into meiosis and characterized by major chromatin reorganizations in haploid spermatids. We report here that a single member of the double bromodomain BET factors, Brdt, is a master regulator of both meiotic divisions and post-meiotic genome repackaging. Upon its activation at the onset of meiosis, Brdt drives and determines the developmental timing of a testis-specific gene expression program. In meiotic cells, Brdt initiates a genuine histone acetylation-guided programming of the genome by activating essential meiotic genes and repressing a M-bM-^@M-^\progenitor cellsM-bM-^@M-^] gene expression program, while M-bM-^@M-^\primingM-bM-^@M-^] a post-meiotic gene group for further activation. At post-meiotic stages, a global chromatin hyperacetylation gives the signal for BrdtM-bM-^@M-^Ys first bromodomain to direct the genome-wide replacement of histones by transition proteins. Brdt is therefore a unique and essential regulator of male germ cell differentiation, which, by using various domains in a developmentally controlled manner, first drives a specific spermatogenic gene expression program, and later controls the tight packaging of the male genome. Examination of Brdt binding on chromatin in meiotic (spermatocytes) and post-meiotic (round spermatids) male germ cells from adult wild type mice

2012-08-30 | E-GEOD-39908 | biostudies-arrayexpress

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