Epigenetic Control of Androgen Production by Histone H2A Lys130 acetylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA852508 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19843967.fastq.gz | Fastqsanger.gz | |||
| SRR19843968.fastq.gz | Fastqsanger.gz | |||
| SRR19843969.fastq.gz | Fastqsanger.gz | |||
| SRR21520543_1.fastq.gz | Fastqsanger.gz | |||
| SRR21520543_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 7 |
Similar Datasets
Project description:The biosynthesis of androgen from cholesterol in testis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncovered that sterol regulatory element-binding protein 1 (SREBP1) and its switch to hitherto unknown dual-phosphorylated form (pY673/951-SREBP1), acts as an androgen sensor. Androgen deficiency promoted SREBP1 dual-phosphorylation, causing its dissociation from androgen receptor (AR) in its androgen-unbound state, followed by nuclear translocation. SREBP1 recruited KAT2A/GCN5 and deposited novel epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Tumor-derived androgen retained SREBP1 in cytosol, promoting T cell exhaustion, reflected in elevated PD-1 and Tim3. Reversal of H2A-K130ac or pY-SREBP1 sensitized castration-resistant prostate cancer (CRPC) resistant to androgen synthesis inhibitor, Abiraterone. Further, nuclear SREBP1 and H2A-K130ac levels were significantly increased and directly correlated with late stage prostate cancer patients. Global lipidomics analysis revealed a distinct lipid signature in androgen-deprived CRPCs, resembling the lipid profile of prostate cancers of African-American (AA) men. Overall, self-perpetuating pY-SREBP1/H2A-K130ac signaling explains sex bias in cancers and reveal a novel therapeutic vulnerability wherein synchronous inhibition of GCN5 and Tyr-kinases could overcome drug-resistant disease, benefiting AA men with aggressive prostate cancer.
2023-05-02 | GSE206856 | GEO
Project description:The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of which sensitizes castration-resistant prostate cancer (CRPC) to androgen synthesis inhibitor, Abiraterone. Further, we identify a distinct CRPC lipid signature resembling lipid profile of prostate cancer in African American (AA) men. Overall, pY-SREBF1/H2A-K130ac signaling explains cancer sex bias and reveal synchronous inhibition of KAT2A and Tyr-kinases as an effective therapeutic strategy.
| S-EPMC10256812 | biostudies-literature
Project description:Histone H2A monoubiquitination is associated with transcriptional repression and needs to be removed by deubiquitinases to facilitate gene transcription in eukaryotes. However, the deubiquitinase responsible for genome-wide H2A deubiquitination in plants has yet to be identified. We found that UBP5, an ubiquitin-specific protease, interacts with a previously identified PEAT (PWWP-EPCR-ARID-TRB) complex to form a larger version of PEAT complex in Arabidopsis thaliana. UBP5 functions as an H2A deubiquitinase in a nucleosome substrate-dependent manner in vitro and mediates H2A deubiquitination at the whole-genome level in vivo. Moreover, our results indicated that the histone acetyltransferases HAM1 and HAM2 (HAM1/2), catalytic subunits of the NuA4 histone acetyltransferase complex, are also part of the PEAT complex at PEAT target genomic loci. Within the PEAT complex, the PWWP components (PWWP1, PWWP2 and PWWP3) directly interact with UBP5 and are necessary for UBP5-mediated H2A deubiquitination, while the EPCR components (EPCR1 and EPCR2) directly interact with HAM1/2 and are required for HAM1/2-mediated H4K5 acetylation. This study identifies previously unknown regulators of H2A deubiquitination and H4K5 acetylation and illustrates how these processes collaborate at the whole-genome level.
2023-10-08 | GSE232671 | GEO
Project description:Histone H2A monoubiquitination is associated with transcriptional repression and needs to be removed by deubiquitinases to facilitate gene transcription in eukaryotes. However, the deubiquitinase responsible for genome-wide H2A deubiquitination in plants has yet to be identified. We found that UBP5, an ubiquitin-specific protease, interacts with a previously identified PEAT (PWWP-EPCR-ARID-TRB) complex to form a larger version of PEAT complex in Arabidopsis thaliana. UBP5 functions as an H2A deubiquitinase in a nucleosome substrate-dependent manner in vitro and mediates H2A deubiquitination at the whole-genome level in vivo. Moreover, our results indicated that the histone acetyltransferases HAM1 and HAM2 (HAM1/2), catalytic subunits of the NuA4 histone acetyltransferase complex, are also part of the PEAT complex at PEAT target genomic loci. Within the PEAT complex, the PWWP components (PWWP1, PWWP2 and PWWP3) directly interact with UBP5 and are necessary for UBP5-mediated H2A deubiquitination, while the EPCR components (EPCR1 and EPCR2) directly interact with HAM1/2 and are required for HAM1/2-mediated H4K5 acetylation. This study identifies previously unknown regulators of H2A deubiquitination and H4K5 acetylation and illustrates how these processes collaborate at the whole-genome level.
2023-10-08 | GSE232670 | GEO
Project description:HAT1 coordinates histone production and acetylation via H4 promoter binding
| PRJNA482252 | ENA
Project description:The energetic costs of duplicating chromatin are large and therefore likely depend on nutrient sensing checkpoints and metabolic inputs. By studying chromatin modifiers regulated by epithelial growth factor, we identified histone acetyltransferase 1 (HAT1) as an induced gene that enhances proliferation through coordinating histone production, acetylation and glucose metabolism. In addition to its canonical role as a cytoplasmic histone H4 acetyltransferase, we isolated a HAT1-containing complex bound specifically at promoters of H4 genes. HAT1-dependent transcription of H4 genes required an acetate-sensitive promoter element. HAT1 expression was critical for S-phase progression and maintenance of H3 lysine 9 acetylation at proliferation-associated genes, including histone genes. Therefore, these data describe a feed-forward circuit whereby HAT1 captures acetyl-groups on nascent histones and drives H4 production by chromatin binding to support chromatin replication and acetylation. These findings have important implications for human disease, since high HAT1 levels associate with poor outcomes across multiple cancer types.
2019-07-02 | GSE117472 | GEO
Project description:Total RNA from three replicate cultures of wild-type and mutant strains was isolated and the expression profiles were determined using Affymetrix arrays. Comparisons between the sample groups allow the identification of genes regulated by the histone H2A K4,7G mutant. Keywords: histone H2A mutant, repeat
2007-10-11 | GSE7338 | GEO
Project description:Histone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.
2023-05-08 | PXD040835 | Pride
Project description:Dual roles of the Arabidopsis PEAT complex in histone H2A deubiquitination and H4K5 acetylation
| PRJNA973557 | ENA
Project description:Total RNA from three replicate cultures of wild-type and mutant strains was isolated and the expression profiles were determined using Affymetrix arrays. Comparisons between the sample groups allow the identification of genes regulated by histone H2A^4-20 mutant. Keywords: histone H2A mutant, repeat
2007-10-11 | GSE7337 | GEO