SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1268445 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Aberrant transcriptional programs mediate malignant transformation of melanoma, the most aggressive form of skin cancer. The lysine methyltransferase SETD6 has been implicated in regulating transcription, cell adhesion, migration, and other processes in various cancers, however its role in melanoma remains unexplored. We recently reported that SETD6 mono-methylates the BRD4 at K99 to selectively regulate transcription of genes involved in mRNA translation. Here, we observed that BRD4 methylation at K99 by SETD6 occurs in melanoma cells. Knockout of SETD6 or a point mutation at BRD4-K99 disrupts BRD4 genomic occupancy. In addition, we show that SETD6 interacts with MITF, a master transcription factor in melanocytes and melanoma, and influences the genomic distribution of MITF. Mechanistically, we uncover a novel chromatin- localized interaction between BRD4 and MITF in melanoma. Our data suggest that BRD4 binds MITF in melanoma cells and that this interaction is dependent on both SETD6-mediated methylation of BRD4 and MITF acetylation. This chromatin complex plays a pivotal role in selective recruitment of BRD4 and MITF to different genomic loci in melanoma cells.
2025-08-20 | GSE298161 | GEO
Project description:Aberrant transcriptional programs mediate malignant transformation of melanoma, the most aggressive form of skin cancer. The lysine methyltransferase SETD6 has been implicated in regulating transcription, cell adhesion, migration, and other processes in various cancers, however its role in melanoma remains unexplored. We recently reported that SETD6 mono-methylates the BRD4 at K99 to selectively regulate transcription of genes involved in mRNA translation. Here, we observed that BRD4 methylation at K99 by SETD6 occurs in melanoma cells. Knockout of SETD6 or a point mutation at BRD4-K99 disrupts BRD4 genomic occupancy. In addition, we show that SETD6 interacts with MITF, a master transcription factor in melanocytes and melanoma, and influences the genomic distribution of MITF. Mechanistically, we uncover a novel chromatin- localized interaction between BRD4 and MITF in melanoma. Our data suggest that BRD4 binds MITF in melanoma cells and that this interaction is dependent on both SETD6-mediated methylation of BRD4 and MITF acetylation. This chromatin complex plays a pivotal role in selective recruitment of BRD4 and MITF to different genomic loci in melanoma cells.
2025-08-20 | GSE298160 | GEO
Project description:SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [CUT&Run]
| PRJNA1268448 | ENA
Project description:MITF, a basic-Helix-Loop-Helix Zipper (bHLHZip) transcription factor, plays vital roles in melanocyte development and functions as an oncogene. We performed a genetic screen for suppressors of the Mitf-associated pigmentation phenotype in mice and identified an intragenic Mitf mutation that terminates MITF at the K316 SUMOylation site, leading to loss of the C-end intrinsically disordered region (IDR). The resulting protein is more nuclear but less stable than wild-type MITF and retains DNA-binding ability. Interestingly, as a dimer, it can translocate wild-type and mutant MITF partners into the nucleus, improving its own stability thus ensuring nuclear MITF supply. To further understand the effect of the suppressor mutation (MITF-sl), we performed CUT&RUN experiments to determine how MITF-sl affects the genome-wide occupancy of MITF. MITF-sl had a higher number of peaks than MITF-WT, with 10,636 peaks (p<0.01) exhibiting statistically significant differences (p < 0.01) between MITF-WT and MITF-sl. Gene ontology analysis indicates that the peaks significantly different between MITF-WT and MITF-sl are associated with genes involved in axonogenesis, axon development, cell growth, and positive regulation of MAPK cascade biological pathways. Our results suggest that the 316-419 domain is critical for selective genome occupancy and transcriptional activation of MITF.
2024-11-06 | GSE267956 | GEO
Project description:Lineage selective cardiac GATA4 chromatin occupancy [embryo]
| PRJNA656292 | ENA
Project description:Skin pigmentation is paused following sun exposure, however the mechanism behind this pausing is unknown. Here we found that the UVB-induced DNA repair system, led by the ATM protein kinase, represses MITF transcriptional activity of pigmentation genes while placing MITF in DNA repair mode, thus directly inhibiting pigment production. Phosphoproteomics analysis revealed ATM to be the most significantly enriched pathway among all UVB-induced DNA repair systems. ATM inhibition in mouse or human skin, either genetically or chemically, induces pigmentation. Upon UVB, MITF transcriptional activation is blocked due to ATM dependent phosphorylation of MITF on S414, which modifies MITF activity and interactome towards DNA repair including binding to TRIM28 and RBBP4. Accordingly, MITF genome-occupancy is enriched in sites of high DNA damage that are likely repaired. This suggests that ATM harnesses the pigmentation key activator, for the necessary rapid, efficient DNA repair, thus optimizing the chances of the cell to survive.
2023-07-19 | PXD041121 | Pride
Project description:Genome-wide occupancy of ZRF1 and BRD4 in neuroblastoma cells.
| PRJNA756174 | ENA
Project description:Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.
2017-05-18 | GSE90444 | GEO
Project description:Neuroblastoma (NB), a malignant embryonic tumor arising from primitive neural crest cells, accounts for more than 7% of malignancies and around 15% of cancer-related mortality in childhood. Better elucidating the mechanisms of tumorigenesis and aggressiveness is important for improving the therapeutic efficiencies of NB. Through integrated proteomics and validating studies, we discovered that ZRF1 and BRD4 form a complex with p113, a novel protein derived from CUX1 circular RNA. To investigate the mechanisms underlying the oncogenic functions of ZRF1 and BRD4, we employed the Illumina Novaseq 6000 as a discovery platform to analyze the genome-wide occupancy of ZRF1 and BRD4 on target genes in human SH-SY5Y cells, while the results were further analyzed with p113-regulated target genes. The results showed that 46 target genes were regulated by transcriptional trimer complex p113/ZRF1/BRD4, especially those involved in metabolic pathway or complex I biogenesis, including ALDH3A1, NDUFA1, and NDUFAF5. Furthermore, we validated the ChIP-seq results by real-time PCR with high identity. Overall, our results provided fundamental information about the genomic enrichment of ZRF1 and BRD4 in human NB cells, and these findings will help us understand the pathogenesis of NB.
2021-10-06 | GSE182402 | GEO
Project description:Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. By tandem affinity purification and mass spectrometry, we present a comprehensive characterisation of the MITF interactome comprising multiple novel cofactors involved in transcription, DNA replication and repair and chromatin organisation, including a BRG1 chromatin remodelling complex comprising CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. MITF, SOX10 and YY1 bind between two BRG1-occupied nucleosomes thus defining both a combinatorial signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of MAREs. Nevertheless, BRG1 silencing enhances MITF occupancy at MAREs showing that BRG1 acts to promote dynamic MITF interactions with chromatin. 8 samples corresponding to genomic occupancy profiling of MITF, SOX10, BRG1 after si-control, BRG1 after si-MITF and BRG1 after siSOX10; and their respective controls (MITF Input, SOX10 Input, GFP-siCTRL ChIPseq) in 501Mel cells.
2015-04-02 | E-GEOD-61965 | biostudies-arrayexpress