DNA Promoter Hypermethylation of Melanocyte Lineage Genes Determines Melanoma Phenotype
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA872536 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte specific gene expression and increase of mesenchymal markers. Two crucial transcription factors, MITF and SOX10, important in melanoma development and progression have been implicated in this process. In this study we describe that loss of MITF is associated with a distinct transcriptional program, MITF promoter hypermethylation and poor patient survival in metastatic melanoma. From a comprehensive collection of melanoma cell lines, we observed that MITF methylated cultures were subdivided in two distinct subtypes. Examining mRNA levels of neural crest associated genes we found that one subtype had lost the expression of several lineage genes including SOX10. Intriguingly, SOX10 loss was associated with SOX10 gene promoter hypermethylation and distinct phenotypic and metastatic properties. Depletion of SOX10 in MITF methylated melanoma cells using CRISPR/Cas9 confirmed these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states.
2022-12-08 | GSE211906 | GEO
Project description:Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug-tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte-specific gene expression and increase of mesenchymal markers. Two crucial transcription factors, microphthalmia-associated transcription factor (MITF) and SRY-box transcription factor 10 (SOX10), important in melanoma development and progression, have been implicated in this process. In this study we describe that loss of MITF is associated with a distinct transcriptional program, MITF promoter hypermethylation, and poor patient survival in metastatic melanoma. From a comprehensive collection of melanoma cell lines, we observed that MITF-methylated cultures were subdivided in 2 distinct subtypes. Examining mRNA levels of neural crest-associated genes, we found that 1 subtype had lost the expression of several lineage genes, including SOX10. Intriguingly, SOX10 loss was associated with SOX10 gene promoter hypermethylation and distinct phenotypic and metastatic properties. Depletion of SOX10 in MITF-methylated melanoma cells using CRISPR/Cas9 supported these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states.
| S-EPMC9675437 | biostudies-literature
Project description:Stem cell establishment and fate assignment are critical for both early development, as well as regeneration. A committed cell state is characterized by its unique transcriptional landscape. In contrast, the upstream fate-biased state is often metastable and transitory, thereby mechanisms of specification are difficult to identify. In this study, we elucidate the role of a histone variant H2a.z.2 in specification of melanocyte lineage from multipotent neural crest cells. Silencing of H2a.z.2 reduces the number of melanocyte precursors in developing zebrafish embryos, and from mouse embryonic stem cells in vitro. We demonstrate that this histone variant occupies nucleosomes in the promoter of key melanocyte determinant Mitf, and enhances its induction. CRISPR-Cas9 based targeted mutagenesis of this gene in zebrafish drastically reduces adult melanocytes, as well as their regeneration. Thereby our study establishes a histone based specification code upstream to the core gene regulatory network in the neural crest lineage leading to melanocytes. This epigenetic code renders the promoter of key determinant in a poised state conducive for activation by external instructive signals and facilitates establishment of downstream cell fate.
2020-03-05 | GSE133141 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE35387: Expression data from normal melanocyte, melanoma cells and their exosomes (microRNA) GSE35388: Expression data from normal melanocyte, melanoma cells and their exosomes (mRNA) Refer to individual Series
2012-10-10 | E-GEOD-35389 | biostudies-arrayexpress
Project description:SMAD1 promoter hypermethylation and lack of SMAD1 expression in Hodgkin Lymphoma
| PRJNA614470 | ENA
Project description:Enhancer-promoter association determines cell specificity in mouse pluripotent cells
| PRJNA475949 | ENA
Project description:Information that regulates gene expression is encoded throughout each gene but if different regulatory regions can be understood in isolation, or if they interact, is unknown. Here we measure mRNA levels for 10,000 open reading frames (ORFs) transcribed from either an inducible or constitutive promoter. We find that the strength of cotranslational regulation on mRNA levels is determined by promoter architecture. By using a novel computational genetic screen of 6402 RNA-seq experiments, we identify the RNA helicase Dbp2 as the mechanism by which cotranslational regulation is reduced specifically for inducible promoters. Finally, we find that for constitutive genes, but not inducible genes, most of the information encoding regulation of mRNA levels in response to changes in growth rate is encoded in the ORF and not in the promoter. Thus, the ORF sequence is a major regulator of gene expression, and a nonlinear interaction between promoters and ORFs determines mRNA levels.
2017-06-28 | GSE100452 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE33092: Oncogenic BRAFV600E remodels the melanocyte transcriptome and induces BLNCR1 to regulate melanoma cell migration [HT-seq] GSE37132: Oncogenic BRAFV600E remodels the melanocyte transcriptome and induces BLNCR1 to regulate melanoma cell migration [Affymetrix] Refer to individual Series
2012-04-27 | E-GEOD-37169 | biostudies-arrayexpress
Project description:The two most common melanoma histopathologic subtypes, superficial spreading (SSM) and nodular melanoma (NM), are believed to represent sequential phases of linear progression from radial to vertical growth. Studies suggest, however, that SSM and NM are biologically distinct. We utilized an integrative genomic approach to examine the possibility that SSM and NM are the result of independent pathways characterized by unique molecular alterations. Cell lines including SSM, NM, metastatic melanoma, and melanocyte controls were evaluated for copy number changes and differential mRNA expression using single nucleotide polymorphism array (SNP 6.0, Affymetrix) and gene array (U133A 2.0, Affymetrix). Data sets were integrated to identify copy number alterations that correlated with gene expression, and array results were validated using immunohistochemistry on human tissue microarrays (TMAs) and an external data set. The functional effect of genomic deletion was assessed by lentiviral overexpression. Integrative genomics revealed 8 genes in which NM/SSM-specific copy number alterations were correlated with NM/SSM differential gene expression (P<0.05, Spearman’s rank). Pathways analysis of differentially expressed genes (N=114) showed enrichment for metabolic-related processes. SSM-specific genomic deletions (DIS3, MTAP, G3BP2, SEC23IP, USO1) were verified in an expanded panel of cell lines, and forced overexpression of MTAP in SSM resulted in reduced cell growth. Metabolism-related gene ALDH7A1 was verified as overexpressed in NM using human TMAs.The identification of recurrent genomic deletions in SSM not present in NM challenges the linear model of melanoma progression and supports the unique molecular classification of SSM and NM. Gene expression profiling using Affymetrix U133A 2.0 arrays was performed on 18 melanoma cell lines including 2 primary superficial spreading melanoma, 2 primary nodular melanoma, 2 metastatic nodular melanoma, and 12 metastatic cell lines. Four melanocyte control lines were also evaluated including 2 immortalized melanocyte cell lines (Hermes 1 and 2B) and 2 normal melanocyte lines cultured from neonatal foreskin (HEM-N and HEM-LP).
2010-12-01 | E-GEOD-22301 | biostudies-arrayexpress
Project description:Histone variant H2A.Z.2 primes MITF promoter to direct specification of melanocyte precursors
| PRJNA550083 | ENA