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SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [CUT&Run]

ABSTRACT: SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [CUT&Run]

PROVIDER: PRJNA1268448 | ENA |

REPOSITORIES: ENA

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SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [CUT&Run]

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.

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SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [RNA-seq]

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Project description:SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [RNA-seq]

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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.

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