Nut directs p300-dependant genome-wide H4 hyperacetylation in male germ cells: transcriptomic data
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ABSTRACT:
PROVIDER: PRJNA487593 | ENA |
REPOSITORIES: ENA
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Project description:NUT, nuclear protein in testis, is a universal oncogenic driver in the highly aggressive NUT Midline Carcinoma whose physiological function in male germ cells had so far remained unknown. Here we show that Nut’s expression is normally restricted to post-meiotic spermatogenic cells, where its presence triggers the p300-dependant genome-wide histone H4 hyperacetylation, which is essential for the completion of histone-to-protamine exchange. Accordingly, the inactivation of Nut induces male sterility with spermatogenesis arrest at the histone removal stage. Molecular investigations show that Nut uses CBP/p300 to enhance acetylation of H4 at both K5 and K8 providing binding sites for the first bromodomain of Brdt, the testis-specific member of the BET family, which subsequently mediates genome-wide histone removal. Altogether, our data reveal the detailed molecular basis of the global histone hyperacetylation wave, which has long been known to occur prior to the final compaction of the male genome.
2018-10-15 | GSE118969 | GEO
Project description:NUT, nuclear protein in testis is the universal fusion partner of BRD4 in the highly aggressive NUT Midline Carcinoma (NMC), but its physiological function is unknown. Here we show that Nut is exclusively expressed in post-meiotic spermatogenic cells, at the time of genome-wide histone hyperacetylation. Inactivation of Nut induces a spermatogenesis arrest at the histone-to-protamine replacement stage, leading to male infertility. Subsequent molecular investigations show that Nut sustains global histone H4 hyperacetylation in post-meiotic cells. Additionally, Nut mediates a p300/CBP-dependent gene expression program and, by enhancing acetylation of H4 at both K5 and K8 sites, provides binding sites for the first bromodomain of Brdt, which drives histone removal. Our results bring the first evidence of Nut’s function in spermatogenic cells where it uses the ubiquitous HATs p300/CBP to direct a cell-type specific histone H4 hyperacetylation. The ectopic activity of Nut in NMC recreates a forced p300-induced histone hyperacetylation / bromodomain-binding loop that normally operates in post-meiotic spermatogenic cells.
2018-10-15 | GSE111931 | GEO
Project description:NUT, nuclear protein in testis is the universal fusion partner of BRD4 in the highly aggressive NUT Midline Carcinoma (NMC), but its physiological function was unknown. Here we show that Nut is exclusively expressed in post-meiotic spermatogenic cells, at the time of genome-wide histone hyperacetylation. Inactivation of Nut induces a spermatogenesis arrest at the histone-to-protamine replacement stage, leading to male infertility. Subsequent molecular investigations show that Nut sustains global histone H4 hyperacetylation in post-meiotic cells. Additionally, Nut mediates a p300/CBP-dependent gene expression program and, by enhancing acetylation of H4 at both K5 and K8 sites, provides binding sites for the first bromodomain of Brdt, which drives histone removal. Nut’s major function is therefore to use the ubiquitous HATs p300/CBP to direct a cell-type specific histone hyperacetylation. Its ectopic activity in NMC recreates a forced p300-induced histone hyperacetylation / bromodomain binding loop that normally operates in post-meiotic spermatogenic cells.
2018-10-02 | PXD008727 | Pride
Project description:Nut is a cell type-specific stimulator of p300 enhancing H4 hyperacetylation during haploid male genome programming
| PRJNA438593 | ENA
Project description:NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET selective bromodomain inhibitors have demonstrated on-target activity in NMC patients, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells in vitro; findings that correspond with potentiated transcriptional effects from combined BET and p300 bromodomain inhibition. In three disseminated NMC xenograft models, NEO2734 provided greater growth inhibition, with tumor regression and significant survival benefit seen in two of three models, compared with a lead clinical BET inhibitor or 'standard' chemotherapy.
2020-06-19 | GSE142481 | GEO
Project description:Discarded live tumor tissue from a metastatic focus in the patientM-bM-^@M-^Ys lung was collected under institutional review board approval through the NUT midline carcinoma registry (www.NMCRegistry.org). From this tissue the first known NUT-variant cell line, 1221, was established. To determine the putative partner gene to NUT, we performed comprehensive RNA-sequencing on RNA purified from 1221. We identified an in-frame transcript fusing the 5M-bM-^@M-^Y coding sequence of NSD3 (exons 1-7) to exons 2-7 of NUT. Expression of the NSD3-NUT fusion oncoprotein was verified by immunobloting with an antibody to NUT, revealing an approximately 200kDa band that is similar in size to BRD3-NUT, but smaller than BRD4-NUT Identification of a NUT fusion partner using RNA extracted from live cultured 1221 cell line derived from a lung metastasis from the index case of a 13 year old female with NUT-positive NMC.
2014-08-01 | E-GEOD-57222 | biostudies-arrayexpress
Project description:Discarded live tumor tissue from a metastatic focus in the patient’s lung was collected under institutional review board approval through the NUT midline carcinoma registry (www.NMCRegistry.org). From this tissue the first known NUT-variant cell line, 1221, was established. To determine the putative partner gene to NUT, we performed comprehensive RNA-sequencing on RNA purified from 1221. We identified an in-frame transcript fusing the 5’ coding sequence of NSD3 (exons 1-7) to exons 2-7 of NUT. Expression of the NSD3-NUT fusion oncoprotein was verified by immunobloting with an antibody to NUT, revealing an approximately 200kDa band that is similar in size to BRD3-NUT, but smaller than BRD4-NUT
2014-08-01 | GSE57222 | GEO
Project description:To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma, we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared to wild type BRD4. Using crosslinking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 among a small number of candidates associated with BRD4-NUT in NMC patient cells but not present in 293T cells.
2017-04-05 | PXD005786 | Pride
Project description:Knockdown of the oncogene, BRD4-NUT, in a rare cancer, termed NUTmidline carcinoma (NMC), results in morphologic features consistent with squamous differentiation. Treatment with the HDAC-inhibitor, TSA, appears to cause the same phenotype. Here, we use gene expression profiling to compare the changes in gene expression following BRD4-NUT knockdown and TSA treatment. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following siRNA knockdown versus control in duplicate. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following treatment with TSA versus etoh control in triplicate
2011-07-01 | E-GEOD-18668 | biostudies-arrayexpress