yueyuan Profile picture
Apr 30, 2021 10 tweets 6 min read Read on X
I’m excited to share our new paper in @NatureComms, just about 11 months after we first shared it on bioRxiv. So thankful for the great help from Guowei Huang and supervision from @benbfly and @dechen_lin. doi.org/10.1038/s41467… Tweetorial follows… [1/10]
When cancer biologists think about CpG Island genes, we typically think about promoter DNA methylation and transcriptional silencing. In our new analysis of pan-cancer TCGA data, we challenge this perception by systematically analyzing changes in this large class of genes. [2/10] Image
Polycomb Repressive Complex 2 binding predisposes CGI genes to methylation and silencing. But in addition to 2,521 PRC2+CGI genes with DNA hypermethylation, we found 1,543 were *upregulated* relative to normal. Their promoters had increased chromatin accessibility & H3K27ac.[3/10 Image
Upregulated PRC2+ genes were often restricted to a specific cancer type or types, and were better than hypermethylated PRC2+ genes or upregulated PRC2- genes at distinguishing between cancer types. [4/10] Image
PRC2+ CGI genes upregulated in one cancer type were frequently methylated in another, such as the WNT antagonist DKK1 which was methylated in Luminal breast cancer but upregulated in the Basal subtype. *Half* of all upregulated PRC2+CGI had this type of plasticity. [5/10] Image
We investigated the mechanism of PRC2+CGI upregulation by comparing to CGI genes without PRC2 binding. PRC2+CGI upregulated genes tended to have transcription factor motifs in distal enhancers (like EFNA2), whereas PRC2- CGI upregulated genes had mostly promoter TF motifs. [6/10] Image
We manipulated TF activity in cancer cells to show that TF enhancer binding is likely responsible for upregulation of genes like EFNA2, mediated by loss of the Polycomb H3K27me3 mark at the promoter. This tracks what's known about PRC2+ regulation in normal differentiation.[7/10]
(...as introduced in this article by @piptaberlay, Peter Jones, Gangning Liang, and others. doi.org/10.1016/j.cell…) [8/10]
We also found that upregulated PRC2+ genes were associated with important functions such as EMT and TNF-α signaling during the inflammatory response. Thus, the inherent regulatory plasticity of this large class of genes allows them to play major roles during tumor evolution.[9/10 Image
This work was possible because of our great institutions @CedarsSinai @CSCancerCare @Hujimed @IMRIC_HUJ @dbcr_huji , and great funders @theNCI @NCIgenomics #TCGA. Thanks! [10/10]

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