EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains

Abstract

Hi-C chromatin maps of EZH2 WT and EZH2 Y646X lymphomas. EZH2 p.Tyr646* gain-of-function alterations lead to a genomewide increase in H3K27me3 (Supplementary Fig. 1a). To establish whether this global accumulation of H3K27me3 modifies the genome topology on a similarly broad scale, we performed high-throughput chromatin conformation capture (Hi-C) in two lymphoma cell lines (Karpas422 and WSU-DLCL2) expressing the mutant form of EZH2 (EZH2 Y646X) and a lymphoma cell line (OCI-Ly19) expressing the wild-type EZH2 (EZH2 WT) protein (Supplementary Table 1 and Supplementary Note). Contact maps of EZH2 Y646X and EZH2 WT cells were binned in regions of 50 kb and compared with multiple metrics (Fig. 1). For each pair of maps, we compared the overall distribution of chromosomal contacts by using the stratum-adjusted correlation coefficient (SCC) 24 (Fig. 1a); the fraction of 1-Mb regions assigned to the same compartment (A or B) 3 (Fig. 1b); the similarity among TADs 25-27 (Fig. 1c); and the fraction of bin interactions that were significant in both maps, also known as the cell interactome 28,29 (Fig. 1d). To build a reference scale of values for each metric, we compared Hi-C maps of EZH2 Y646X lymphoma cell lines with Hi-C maps of endothelial cells (HUVEC), fetal fibroblasts (IMR90), and normal lymphoblastoid cells (GM12878). Moreover, we used randomized contact maps or

Wapl releases Scc1-cohesin and regulates chromosome structure and segregation in mouse oocytes

“…S3 C). The former likely reflects loss of loops and TADs, whereas the latter might reflect long-range polycomb interactions, which have recently been observed in other cell types (Donaldson-Collier et al, 2019; Wang et al, 2018; Rhodes et al, 2020; Ogiyama et al, 2018; Du et al, 2020). The first maximum of the slope derivative reflects the average loop size, which increases from 390 kbp in Scc1 fl/fl to 1.6 Mbp in Scc1 Δ/Δ oocytes.…”

<p>Silencing Of hsa_circ_0008450 Represses Hepatocellular Carcinoma Progression Through Regulation Of microRNA-214-3p/EZH2 Axis</p>

“…20 Enhancer of zeste 2 homolog (EZH2) is the catalytic subunit of the polycomb repressive complex 2, which is a complex that methylates lysine 27 of histone H3 (H3K27) to repress its gene expression. [21][22][23] Meanwhile, EZH2 has been well studied in tumor progression, such as breast cancer, 24 prostate cancer, 25 and colorectal cancer. 26 Intriguingly, EZH2 was also reported to be a critical regulator of circRNA in cancers.…”

EZH2 inhibitors-mediated epigenetic reactivation of FOSB inhibits triple-negative breast cancer progress

“…High levels of EZH2 were shown to correlate with aggressiveness and advanced disease in each of these cancer types [10]. EZH2 has been shown to be essential for proliferation of cancer cell lines that is largely dependent upon its methyltransferase domain [14]. Forced expression of EZH2 leads to neoplastic transformation of breast epithelial cells and development of myeloproliferative disorder in mice [15].…”