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Cell-type specific meQTL extends melanoma GWAS annotation beyond eQTL and identifies a melanocyte gene regulatory network

ABSTRACT: To explore the roles of cell-type specific methylation QTL (meQTL) for melanoma GWAS annotation, we generated DNA methylation data from the same sample set as our previouse eQTL study including 106 primary melanocyte cultures. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 480,000 CpGs in 106 primary melanocyte cultures. To be able to identify the DNA methylation probes whose methylation levels are correlated with germline genetic variants including the ones associated with melanoma, meQTL analysis was performed in these 106 primary melanocyte cultures using the same method as we did for eQTL study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166069 | GEO | 2021/10/01

REPOSITORIES: GEO

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Project description:Melanoma genomes are often characterized by large numbers of sunlight-induced mutations. However, epigenetic alterations, in the form of aberrant DNA methylation patterns, are also abundant. Using MIRA-seq, we have carried out a comprehensive characterization of the DNA methylome in a series of metastatic melanoma samples and catalogued the methylation changes relative to normal melanocytes, the presumed cells of origin for these tumors. Individual melanoma tumors contained up to several thousand hypermethylated regions. We discovered 179 tumor-specific methylation peaks that were present in all (27/27) melanomas and may lend themselves as effective disease biomarkers, and 3124 methylation peaks were present in >40% of the tumors. We specifically examined the relationship between presence of the Polycomb mark, H3K27me3 in melanocytes and tumor-specific DNA methylation in melanoma. We found that 150 of the approximately 1,200 tumor-associated methylation peaks near transcription start sites (TSS) were H3K27me3-marked in melanocytes. Notably, DNA methylation in melanoma was specific for distinct H3K27me3 peaks rather than for H3K27me3-enriched regions with broad genomic coverage. Yet, there were also numerous H3K27me3 peak-associated TSS regions that were completely resistant to DNA methylation in tumors. Furthermore, a rather large group of genes became methylated in melanoma but lacked H3K27me3 in melanocytes. There was no relationship between presence of BRAF V600 mutations and the number of methylation peaks in individual tumors. Gene expression analysis showed a strong signature of upregulated immune response genes in melanomas presumably as a result of lymphocyte infiltration. Genes down-regulated in tumors were enriched for melanocyte differentiation and pigmentation factors. Overall, there was limited correlation between tumor-associated DNA methylation changes and changes in gene expression although distinct melanocyte differentiation genes including KIT, PAX3 and SOX10 became methylated and downregulated in melanoma. Using MIRA-Seq, DNA methylation profiles of 27 malignant melanomas and 3 primary cultured melanocyte samples were determined

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Cell-type specific meQTL extends melanoma GWAS annotation beyond eQTL and identifies a melanocyte gene regulatory network

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