ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming
Fei Li, … , Yu Chen, Dong Gao
Fei Li, … , Yu Chen, Dong Gao
Published July 23, 2020
Citation Information: J Clin Invest. 2020;130(11):5924-5941. https://doi.org/10.1172/JCI137967.
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Research Article Cell biology Oncology

ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming

Abstract

Although cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early-stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer proluminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we found that ERG was highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibited those cells’ normal plasticity to transdifferentiate into a basal lineage, and ERG superseded PTEN loss, which favored basal differentiation. ERG KO disrupted prostate cell luminal differentiation, whereas AR KO had no such effects. Trp63 is a known master regulator of the prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG bound and inhibited the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG, in its fundamental role in lineage differentiation in prostate cancer initiation, orchestrated chromatin interactions and regulated prostate cell lineage toward a proluminal program.

Authors

Fei Li, Qiuyue Yuan, Wei Di, Xinyi Xia, Zhuang Liu, Ninghui Mao, Lin Li, Chunfeng Li, Juan He, Yunguang Li, Wangxin Guo, Xiaoyu Zhang, Yiqin Zhu, Rebiguli Aji, Shangqian Wang, Xinyuan Tong, Hongbin Ji, Ping Chi, Brett Carver, Yong Wang, Yu Chen, Dong Gao

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Figure 9

Deletion of a specific ERG binding site impaired the function of ERG in prostate lineage regulation.

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Deletion of a specific ERG binding site impaired the function of ERG in ...
(A) 3D signal of BL-Hi-C showing chromatin interactions of Trp63 loci and its neighboring gene Leprel1 loci in Pten–/– (top) and Pten–/– R26ERG (bottom) organoids; red box indicates the highly interacting region of Trp63 loci, blue box indicates the highly interacting region of Leprel1 loci. (B) 3D signal of BL-Hi-C showing chromatin interactions between the distal ERG binding site and Trp63 gene body region in Pten–/– (top) and Pten–/ R26ERG (bottom) organoids. Red arrow indicates the distal ERG binding site. (C) Pearson’s χ2 test to evaluate the differences of interaction loops density between Pten–/– and Pten–/– R26ERG organoids. (D) qRT-PCR analysis of Trp63, Krt8, and Krt18 mRNA expression in EB-KO and control of Pten–/– R26ERG organoids (2-tailed t test, mean ± SEM, n = 3). (E) Heatmap of RNA-Seq for EB-KO and control of Pten–/– R26ERG organoids using differentially expressed prostate cell lineage signature genes. (F) GSEA enrichment plot of EB-KO organoids versus control organoids using ERG-downregulating basal cell signature genes (left) and ERG-upregulating luminal cell signature genes (right). (G) ERG, Trp63, Krt8, and DAPI IF staining for allografts of UGSM tissue recombination assays derived from EB-KO and control organoids; red arrows indicate ERG+Trp63+ cells. (H) Quantification statistics for the percentage of ERG+Trp63+ in ERG+ prostate cells (analyses were performed based on 3239 ERG+ cells of EB-KO and 3806 ERG+ cells of control, 2-tailed t test, mean ± SEM, n = 5). Scale bars: 50 μm.