The Epigenetic Landscape of Intestinal Tumors and the Role of Polycomb Repressive Complex 2
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Kang, Yun Jee
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CitationKang, Yun Jee. 2020. The Epigenetic Landscape of Intestinal Tumors and the Role of Polycomb Repressive Complex 2. Doctoral dissertation, Harvard Medical School.
AbstractEpigenetic mechanisms regulate gene expression programs, and consequently, cell fate specification. DNA methylation, histone modifications, and chromatin structure remodeling represent epigenetic changes that can interact to alter cellular phenotypes and persist following cell division. Dysregulation of such processes has been recognized to influence hundreds of genes and to cooperate with genetic perturbations in enabling tumorigenesis. Polycomb repressive complex 2 (PRC2) is an epigenetic regulator with altered expression in multiple cancers, including prostate, bladder, and colorectal cancer. PRC2 is comprised of two stabilizing core proteins, SUZ12 and EED, and two methyltransferases, EZH1 and EZH2, which methylate lysine 27 of histone 3; trimethylation of this residue (H3K27me3) is associated with gene repression. However, the molecular mechanisms underlying the relationship between these marks, or other effects of PRC2, and cancer remain unclear.
To study the effect of PRC2 on H3K27me3, gene expression, and tumorigenesis in colorectal cancer, we used murine models of intestinal adenomas induced by Wnt pathway activation (APC KO) in Lgr5+ stem cells. Our results suggest a role for H3K27me3 modulation in tumorigenesis. ChIP-seq analysis of the Lgr5+ cancer stem cells and wildtype Lgr5+ intestinal stem cells led to the identification of 4,377 genes with significantly different H3K27me3 levels (q <0.02) within the gene body, including the promoter region; of these, 1,316 demonstrated corresponding gene expression changes from differential RNA-seq analysis. This profound alteration in both the H3K27me3 profile and the transcriptome of cancer stem cells indicates that knocking out APC has a much greater role in globally dysregulating the cell state than previously appreciated, and that many of these changes may be associated with PRC2.
We also generated mice with intestinal adenomas with decreased or increased PRC2 activity by deleting Eed or overexpressing EZH2, respectively. PRC2 modulation has a significant effect on tumorigenesis, with EZH2 overexpression in leading to decreased tumor burden in our mouse models compared to both wildtype PRC2 mice and Eed-null mice. Further work in analyzing RNA-seq data gathered from each of the models, together with more detailed phenotypic characterization of each model, also revealed how PRC2 disruption drives aberrant gene expression programs associated with tumorigenesis.
Thus, our data provides novel evidence supporting the hypothesis that PRC2 modulation may perturb the tumor phenotype by disrupting physiologic histone methylation and instigating aberrant transcriptional programs. Given the strong links between PRC2 expression and cancer, additional studies are needed to determine how PRC2 expression and the resulting distribution of H3K27me3 modulate tumor phenotypes.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37364791