乙酰化
表观遗传学
染色质
增强子
重编程
组蛋白
基因沉默
转录组
黑色素瘤
二价染色质
癌症研究
表型
表观遗传学
遗传学
生物
基因表达
DNA甲基化
染色质重塑
基因
作者
Karen Mendelson,Tiphaine Martin,Christie B Nguyen,Min Hsu,Jing Xu,Claudia Lang,Reinhard Dummer,Yvonne M. Saenger,Jane L. Messina,Vernon K. Sondak,Garrett Desman,Dan Hasson,Emily Bernstein,Ramon Parsons,Jülide Tok Çelebi
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2024-02-06
标识
DOI:10.1172/jci.insight.166611
摘要
Dedifferentiation or phenotype switching refers to the transition from a proliferative to an invasive cellular state. We previously identified a 122-gene epigenetic gene signature that classifies primary melanomas as low versus high risk (denoted as Epgn1 or Epgn3). We found that the transcriptomes of the Epgn1 low-risk and Epgn3 high-risk cells are similar to the proliferative and invasive cellular states, respectively. These signatures were further validated in melanoma tumor samples. Examination of the chromatin landscape revealed differential H3K27 acetylation in the Epgn1 low-risk versus Epgn3 high-risk cell lines that corroborated with a differential super-enhancer and enhancer landscape. Melanocytic lineage genes (MITF, its targets and regulators) were associated with super-enhancers in the Epgn1 low-risk state, whereas invasiveness genes were linked with Epgn3 high-risk status. We identified the ITGA3 gene as marked by a super-enhancer element in the Epgn3 invasive cells. Silencing of ITGA3 enhanced invasiveness in both in vitro and in vivo systems, suggesting it as a negative regulator of invasion. In conclusion, we define chromatin landscape changes associated with Epgn1/Epgn3 and phenotype switching during early steps of melanoma progression that regulate transcriptional reprogramming. This super-enhancer and enhancer-driven epigenetic regulatory mechanism resulting in major changes in the transcriptome could be important in future therapeutic targeting efforts.
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