مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Role of H3K4me3 in Oncogene Activation in Melanoma Cells
Role of H3K4me3 in Oncogene Activation in Melanoma Cells
Fereshteh Chitsazian,1,*Roshanak Shabandost,2Hamidreza Erfanian,3
1. Biological Department, Research Center for Development of Advanced Technologies, Tehran, Iran 2. Bioinformatics Department, University of Science and Culture, Tehran, Iran 3. Bioinformatics Department, University of Science and Culture, Tehran, Iran
Introduction: Melanoma is one of the deadliest forms of skin cancer, with its global incidence rising sharply in recent decades—claiming one life every 57 minutes. Early diagnosis and treatment can lead to successful surgical removal, but current diagnostic methods, including visual inspection and histopathological image analysis, are often subjective and prone to error. Computational tools for automated melanoma detection are therefore essential.
Following the completion of the Human Genome Project, researchers discovered that DNA sequence alone cannot fully explain phenotypic variation. Epigenetic factors, particularly histone modifications, play a crucial role in gene expression regulation. These modifications—such as acetylation and methylation—alter chromatin structure and influence gene activity. Importantly, histone marks often act in combination rather than isolation, and their collective patterns determine transcriptional outcomes.
Integrative analysis of epigenomic and transcriptomic data has revealed correlations between chromatin changes and gene expression differences in tumor versus non-tumor cells. These epigenetic alterations may contribute to cancer plasticity and resistance to therapy. While previous studies have examined individual histone marks at gene promoters, little is known about their roles at gene termini.
This study aims to identify combinatorial histone mark patterns specifically H3K4me3 and their impact on gene expression in melanoma cells. By analyzing genome-wide histone modification and gene expression data from tumor and non-tumor melanocytes, we identified differentially expressed genes and their associated histone mark profiles. The goal is to uncover epigenetic signatures that drive oncogene activation and tumorigenesis in melanoma.
Methods: Histone modification data for melanoma and normal melanocyte cells were downloaded from GEO (GSE33930), including expression profiles and two histone marks: H3K4me3 and H3K27me3, analyzed via ChIP-Seq. The gene expression data (GSE38312) were retrieved for both cell types. Expression data were processed using Console Expression, while histone modification data were analyzed through MATLAB coding. The datasets were integrated to identify histone mark patterns at gene promoters and termini of significantly altered genes. Differentially expressed genes between melanoma and normal cells were further examined using STRING to explore functional interactions and epigenetic regulation contributing to melanoma development.
Results: Histone modifications are increasingly recognized as key epigenetic mechanisms that regulate chromatin structure and gene expression. This study investigated the role of two histone modifications—H3K4me3 and H3K27me3—on gene expression at the promoter and terminator regions. Ten genes with the highest upregulation and ten with the most significant downregulation in melanoma cells compared to normal melanocytes were identified. The abundance of H3K4me3 and H3K27me3 at the start and end of these genes was analyzed.
H3K4me3 was found to be enriched at the promoter regions of upregulated genes, doubling in intensity and contributing to their activation. Conversely, in downregulated genes, H3K4me3 levels at the promoter decreased by 30%. Interestingly, H3K4me3 showed no significant change at the gene termini of upregulated genes in melanoma cells. H3K27me3 levels at the promoter regions were reduced in both upregulated and downregulated genes, while its abundance at the gene ends remained largely unchanged.
Conclusion: This study highlights the pivotal role of histone modifications—specifically H3K4me3 and H3K27me3—in regulating gene expression in melanoma cells. By integrating gene expression and epigenetic data from normal melanocytes and melanoma cell lines, we identified distinct histone mark patterns associated with upregulated and downregulated genes. Our findings demonstrate that H3K4me3 is significantly enriched at the promoter regions of upregulated genes, suggesting its activating role in oncogene expression, while its reduction in downregulated genes further supports its regulatory influence. In contrast, H3K27me3 showed a general decrease at promoter regions regardless of gene expression status, indicating a more complex or context-dependent role. These insights into histone mark dynamics at gene boundaries provide a deeper understanding of melanoma epigenetics and may contribute to the development of targeted therapeutic strategies based on chromatin remodeling.