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Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation  Martin Lauss, Rizwan Haq, Helena Cirenajwis,

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Presentation on theme: "Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation  Martin Lauss, Rizwan Haq, Helena Cirenajwis,"— Presentation transcript:

1 Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation  Martin Lauss, Rizwan Haq, Helena Cirenajwis, Bengt Phung, Katja Harbst, Johan Staaf, Frida Rosengren, Karolina Holm, Mattias Aine, Karin Jirström, Åke Borg, Christian Busch, Jürgen Geisler, Per E. Lønning, Markus Ringnér, Jillian Howlin, David E. Fisher, Göran Jönsson  Journal of Investigative Dermatology  Volume 135, Issue 7, Pages (July 2015) DOI: /jid Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 DNA methylation patterns in melanoma. (a) Location of hypomethylated and hypermethylated CpGs, as well as all platform CpGs in respect to genes and CpG island annotations (left panel). Functional enrichment of genes that contain hypermethylated CpGs (right panel). For a given set of CpGs (all/hypometh./hypermeth.), a bar indicates the fraction of CpGs assigned to the respective annotation. TSS1500=1,500 to 201bp upstream of transcription start, TSS200=200bp to transcription start site, Body=gene body. PRC2-targets=set of genes that are targeted by histone H3K27-methylating complex PRC2 (Leeet al. (2006)). (b) DNA methylation characteristics across 50 melanomas; mean of β-values (left) and standard deviation of β-values (right) along the genes. Meth., methylated. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 Correlation of gene methylation status and gene expression levels in microphthalmia–associated transcription factor (MITF) and MITF targets. For the CpG with the largest negative correlation value in MITF (a), and its target genes MLANA (b) and TYR (c), β-values are plotted against gene expression values for the respective gene. In each plot, dots represent individual tumors and are colored according to gene expression phenotype. Methylation levels of light (orange), medium (dark red), and dark (brown) melanocytes are shown as dashed lines. Below each plot the gene structure and position of each measured CpG is shown. CpGs with significant correlation between methylation and gene expression are labeled red (an asterisk indicates one of the three significant CpGs in MLANA). Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 DNA methylation status of microphthalmia–associated transcription factor (MITF) and MITF pathway genes. Tumors in the Bergen and TCGA cohorts are ordered according to MITF gene expression. MITF and selected MITF target genes are plotted and CpGs are ordered according to genomic position. An asterisk indicates CpGs with significant negative correlation between methylation and gene expression and TSS regions (±1,500bp from TSS) that include significant CpGs are marked by an orange line. The methylation status for normal cells is also shown. TCGA, The Cancer Genome Atlas data; TSS, transcription start site. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

5 Figure 4 Correlation of gene methylation status and gene expression levels in the Bergen and TCGA, The Cancer Genome Atlas data (TCGA) cohorts. Each dot represents a CpG’s correlation to gene expression. MITF, microphthalmia–associated transcription factor. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

6 Figure 5 Microphthalmia–associated transcription factor (MITF) pathway methylation in melanoma cell lines. (a) Correlation of gene methylation status and gene expression levels in the Bergen and cell line cohorts. Each dot represents a CpG’s correlation to gene expression. (b) DNA methylation status of CpGs covering the genes MITF, MLANA, TYR, BCL2, and RAB27A across all melanoma cell lines and normal cells (melanocytes, keratinocytes, dermal fibroblasts, and lymphocytes). CpGs are ordered according to genomic position. TSS regions (±1,500bp from TSS) that include significant CpGs are marked by an orange line. Furthermore, the DNA methylation status of cg in the MITF-M TSS was fully validated using bisulfite Sanger sequencing. (c) Microarray gene expression values for the selected MITF genes in all melanoma cell lines. Expression values are also shown for WM852 and MM383 cells overexpressing MITF. Notably, MITF gene expression was not measured, as the probe on the array is located outside of the MITF-M insert. (d) MITF immunohistochemistry in melanoma cell lines with varying levels of MITF. TSS, transcription start site. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

7 Figure 6 Microphthalmia–associated transcription factor (MITF) expression and activity is regulated by CpG methylation. (a) Bisulphite Sanger sequencing confirms demethylation of the MITF-M promoter in MM383 and WM852 cells treated with 5μM 5-Aza. (b) Western blot analysis of MITF-M following 5-Aza treatment for 96 hours in MM383 and WM852 cell lines. (c) Proliferation and invasion assays showing 5-Aza effects on WM852 cells. The Invasion assay was performed after 96 hours. (d) Proliferation and invasion assays showing 5-Aza and BRAF inhibition (BRAFi) effects on MM383 cells. Left plot shows proliferative capacity of MM383 cells treated with 5-Aza, BRAFi, or the combination. Right plot shows invasive capacity of MM383 cells treated with 5-Aza, BRAFi, or the combination. (e) Western blot analysis of MITF-M and MLANA following 5-Aza treatment for 96 hours in MM383 and WM852 cell lines with and without exogenous overexpression of MITF-M. As a control, protein lysate from SK-MEL-3 was included. (f) Bisulphite Sanger sequencing confirms demethylation of the MITF-M promoter in MM383-MITF-M+ and WM852-MITF-M+ cells treated with 5-Aza. Adenosine, green; cytosine, blue; guanine, black; thymidine, red. 5-Aza, 5′-Aza-2′-Deoxycytidine. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

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