Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

Autor(es)

Azevedo, Hatylas ; Pessoa, Guilherme Cavalcante ; de Luna Vitorino, Francisca Nathalia ; Nsengimana, Jeremie ; Newton-Bishop, Julia ; Reis, Eduardo Moraes ; da Cunha, Julia Pinheiro Chagas ; Jasiulionis, Miriam Galvonas

• Tipo de documento: Artigo Científico
• Fonte: CLINICAL EPIGENETICS; v. 12, n. 1, p. 24-pg., 2020-08-24.

Resumo

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. Conclusions We uncovered transcriptional and histone modification signatures that may be molecular events driving melanoma progression and metastasis, which can aid in the identification of novel prognostic genes and drug targets for treating the disease. (AU)

• Processo FAPESP: 17/18344-9 - Proteômica quantitativa da cromatina frente ao tratamento com FGF2: análise da regulação transcricional e associação de cdc42
• Beneficiário: Francisca Nathália de Luna Vitorino
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 18/15553-9 - Indo a fundo na regulação da cromatina de Trypanosoma cruzi: identificação de novas moléculas e questionando seu possível impacto no controle da transcrição
• Beneficiário: Julia Pinheiro Chagas da Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2
• Processo FAPESP: 18/20775-0 - RNAs não codificantes envolvidos com a gênese e a progressão do melanoma
• Beneficiário: Miriam Galvonas Jasiulionis
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/13663-0 - Integração de dados de expressão de genes e microRNAs, metiloma e hidroximetiloma de diferentes etapas da progressão do melanoma.
• Beneficiário: Miriam Galvonas Jasiulionis
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/04254-0 - Perfil global de marcas em histonas em etapas distintas da progressão do melanoma e seu impacto em características de malignidade
• Beneficiário: Guilherme Cavalcante Pessoa
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica