Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchym
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RESEARCH
Open Access
Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-tomesenchymal transition, and metastasis Hátylas Azevedo1†, Guilherme Cavalcante Pessoa2†, Francisca Nathália de Luna Vitorino3, Jérémie Nsengimana4,5, Julia Newton-Bishop4, Eduardo Moraes Reis6, Júlia Pinheiro Chagas da Cunha3† and Miriam Galvonas Jasiulionis2*†
Abstract Background: We have previously developed a murine cellular system that models the transformation from melanocytes to metastatic melanoma cells. This model was established by cycles of anchorage impediment of melanocytes and consists of four cell lines: differentiated melanocytes (melan-a), pre-malignant melanocytes (4C), malignant (4C11−), and metastasis-prone (4C11+) melanoma cells. Here, we searched for transcriptional and epigenetic signatures associated with melanoma progression and metastasis by performing a gene co-expression analysis of transcriptome data and a mass-spectrometry-based profiling of histone modifications in this model. Results: Eighteen modules of co-expressed genes were identified, and some of them were associated with melanoma progression, epithelial-to-mesenchymal transition (EMT), and metastasis. The genes in these modules participate in biological processes like focal adhesion, cell migration, extracellular matrix organization, endocytosis, cell cycle, DNA repair, protein ubiquitination, and autophagy. Modules and hub signatures related to EMT and metastasis (turquoise, green yellow, and yellow) were significantly enriched in genes associated to patient survival in two independent melanoma cohorts (TCGA and Leeds), suggesting they could be sources of novel prognostic biomarkers. Clusters of histone modifications were also linked to melanoma progression, EMT, and metastasis. Reduced levels of H4K5ac and H4K8ac marks were seen in the pre-malignant and tumorigenic cell lines, whereas the methylation patterns of H3K4, H3K56, and H4K20 were related to EMT. Moreover, the metastatic 4C11+ cell line showed higher H3K9me2 and H3K36me3 methylation, lower H3K18me1, H3K23me1, H3K79me2, and H3K36me2 marks and, in agreement, downregulation of the H3K36me2 methyltransferase Nsd1. (Continued on next page)
* Correspondence: [email protected] † Hátylas Azevedo and Guilherme Cavalcante Pessoa are First authors that contributed equally to this paper. † Júlia Pinheiro Chagas da Cunha and Miriam Galvonas Jasiulionis are Senior authors that contributed equally to this work. 2 Department of Pharmacology, Universidade Federal de São Paulo (UNIFESP), Rua Pedro de Toledo 669 5 andar, Vila Clementino, São Paulo, SP 04039032, Brazil Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to
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