SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [CUT&Run]
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PROVIDER: PRJNA1268448 | ENA |
REPOSITORIES: ENA
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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 [RNA-seq]
| PRJNA1268445 | ENA
Project description:The SETD6 protein lysine methyltransferase has a role in the regulation of various cellular processes including cancer initiation and progression. It methylates several cellular proteins including K117 of the E2F1 transcription factor, but the functional consequences of this methylation event are unknown. In this study, the role of SETD6 mediated E2F1 methylation on the progression of prostate cancer was investigated. We identified distinct sets of genes that are bound and upregulated by methylated and unmethylated E2F1. Genes upregulated by methylated E2F1 lead to the negative regulation of cell migration, while genes upregulated by unmethylated E2F1 have roles in cell proliferation and apoptosis. BRD4 is known to bind E2F1 acetylated at K117 and K120. Here, we demonstrate that methylation of E2F1 at K117 prevents E2F1-BRD4 binding of in vitro and in cells establishing the molecular mechanism of the differential gene regulation by methylated and unmethylated E2F1 that depends on SETD6 activity.
2025-12-22 | GSE286198 | GEO
Project description:The SETD6 protein lysine methyltransferase has a role in the regulation of various cellular processes including cancer initiation and progression. It methylates several cellular proteins including K117 of the E2F1 transcription factor, but the functional consequences of this methylation event are unknown. In this study, the role of SETD6 mediated E2F1 methylation on the progression of prostate cancer was investigated. We identified distinct sets of genes that are bound and upregulated by methylated and unmethylated E2F1. Genes upregulated by methylated E2F1 lead to the negative regulation of cell migration, while genes upregulated by unmethylated E2F1 have roles in cell proliferation and apoptosis. BRD4 is known to bind E2F1 acetylated at K117 and K120. Here, we demonstrate that methylation of E2F1 at K117 prevents E2F1-BRD4 binding of in vitro and in cells establishing the molecular mechanism of the differential gene regulation by methylated and unmethylated E2F1 that depends on SETD6 activity.
2025-12-22 | GSE286020 | GEO
Project description:ATAC-seq performed to identify chromatin accessibility across the genome. CUT&RUN-seq was performed to identify and compare transcription factor and histone mark occupancy across genome of WT and MITF and TFE3 KO cells.
2025-03-20 | GSE273815 | GEO
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:To investigate the role of BRD4 in normal hematopoiesis, Brd4 conditional KO mouse model was generated. We purified the Lin-cKit+ cells from bone marrow of WT and Brd4 KO mice and performed the CUT&RUN to study the histone modification and Brd4 occupancy around genome in HSC/HPCs population.
2023-08-20 | GSE189833 | GEO
Project description:The goal of this study was to identifiy shared target genes for SETD3 and SETD6.
2023-03-01 | GSE199250 | GEO
Project description:The transcriptional coactivator BRD4 has a fundamental role in transcription regulation and thus became a promising epigenetic therapeutic candidate to target diverse pathologies. However, the regulation of BRD4 by posttranslational modifications has been largely unexplored. Here, we show that BRD4 is methylated on chromatin at lysine-99 by the protein lysine methyltransferase SETD6. BRD4 methylation negatively regulates the expression of genes that are involved in translation and inhibits total mRNA translation in cells. Mechanistically, we provide evidence that supports a model where BRD4 methylation by SETD6 does not have a direct role in the association with acetylated histone H4 at chromatin. However, this methylation specifically determines the recruitment of the transcription factor E2F1 to selected target genes that are involved in mRNA translation. Together, our findings reveal a previously unknown molecular mechanism for BRD4 methylation-dependent gene-specific targeting, which may serve as a new direction for the development of therapeutic applications.
| S-EPMC8153730 | biostudies-literature