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INO80 governs super-enhancer-mediated oncogenic transcription and tumor growth in melanoma [ChIP-seq_NextSeq]

ABSTRACT: Super-enhancers (SEs) are large genomic regions with high density of enhancer marks. In cancer, SEs are found near oncogenes and dictate cancer gene expression. However, how oncogenic SEs are regulated remains poorly understood. Here, we show that INO80, a chromatin remodeling complex, is required for SE-mediated oncogenic transcription and tumor growth in melanoma. The expression of Ino80, the SWI/SNF ATPase, is elevated in melanoma cells and patient melanomas compared to normal melanocytes and benign nevi. Furthermore, Ino80 silencing selectively inhibits melanoma cell proliferation, anchorage-independent growth, as well as tumorigenesis and tumor maintenance in mouse xenografts. Mechanistically, Ino80 occupies more than 90% of SEs, and its occupancy is dependent on transcription factors such as MITF and Sox9. Ino80 binding reduces nucleosome occupancy and facilitates Mediator recruitment, thus promoting oncogenic transcription. Consistently, genes co-occupied by Ino80 and Med1 are specifically expressed in melanomas compared to melanocytes. Together, our results reveal an essential role of INO80-dependent chromatin remodeling in SE function, and suggest a novel strategy for disrupting SEs in cancer treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE82332 | GEO | 2016/07/07

SECONDARY ACCESSION(S): PRJNA328057

REPOSITORIES: GEO

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Project description:Melanoma is the deadliest form of skin cancer with rising incidence and mortality rates. Oncogenic mutation in BRAF gene is the single most frequent genetic alteration in human melanoma; however, this event per se is not sufficient to produce melanoma in vivo. We have investigated whether epigenetic changes, specifically aberrant DNA methylation and dysregulation of gene expression, alone or in combination with this genetic event, are involved in the genesis of human melanoma. We have constructed the whole M-bM-^@M-^XM-bM-^@M-^Xof primary human melanomas in relation to their BRAF mutational status. Our methylation profiling identified a large number of hyper- or hypomethylated genes in melanoma tumors, many of which being novel and having the potential to serve as biomarkers. Gene ontology analysis revealed that gene categories involved in neuronal cell morphology and development, and skin and neurological disorders were highly enriched. Frequently methylated targets included developmental regulatory transcription factors and homeobox genes, which are mostly subjected to bivalent histone marking and Polycomb occupancy in embryonic stem cells. Notably, several genes involved in the MEK-ERK and the PI3K pathways, two of the most frequently perturbed pathways in human melanoma, showed extensive methylation changes. Gene expression profiling identified a long list of dysregulated genes, many of which being involved in melanocytes development and differentiation, and showing concomitant aberrant DNA methylation. Sub-typing of the melanoma tumors based on BRAF mutational status revealed that tumors with a mutated BRAF had distinctive and more pronounced changes in both DNA methylation and gene expression profiles than tumors carrying the wildtype BRAF. The differentially compromised methylome and transcriptome of melanomas (dependent on BRAF mutation) deserves special attention because many epigenetic alterations, including DNA methylation-mediated regulation of gene expression, are potentially reversible. The dichotomous integrity of epigenome in human melanoma holds great promise for the field of personalized medicine. Methylome: Eleven primary human melanoma speciemens versus five normal human melanocyte samples. Transcriptome: Ten primary human melanoma speciemens versus four normal human melanocyte samples

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INO80 governs super-enhancer-mediated oncogenic transcription and tumor growth in melanoma [ChIP-seq_NextSeq]

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