Project description:Gene regulatory networks are pivotal for many biological processes. In mouse embryonic stem cells (mESCs) the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core and Myc. The Polycomb module represses developmental genes, while the Myc module is associated with proliferative functions and its mis-regulation is linked to cancer development. Here, we show that in mESCs the Polycomb Repressive Complex 2 (PRC2) associated protein EPOP (a.k.a C17orf96, esPRC2p48, E130012A19Rik) co-localizes at chromatin with members of the Myc and Polycomb module. EPOP interacts with the transcription elongation factor Elongin BC and the H2B deubiquitinase USP7 to modulate transcriptional processes in mESCs similar to MYC. EPOP is commonly up-regulated in human cancer and we demonstrate that its loss impairs the proliferation of several human cancer cell lines. Our findings establish EPOP as a unique modulator of transcriptional processes, impacting both Polycomb and active gene transcription in mammalian cells.

2016-11-17 | GSE85681 | GEO

EPOP interacts with Elongin BC and USP7 to modulate the chromatin landscape (EPOP KO)

2016-11-17 | GSE76536 | GEO

EPOP interacts with Elongin BC and USP7 to modulate the chromatin landscape (Elongin B KO)

2016-11-17 | GSE79318 | GEO

EPOP Functionally Links Elongin and Polycomb in Pluripotent Stem Cells

Project description:The cellular plasticity of pluripotent stem cells is thought to be sustained by genomic regions that display both active and repressive chromatin properties. These regions exhibit low levels of gene expression, yet the mechanisms controlling these levels remain unknown. Here, we describe Elongin BC as a binding factor at the promoters of bivalent sites. Biochemical and genome-wide analysis shows that Elongin BC is associated with Polycomb Repressive Complex 2 (PRC2) in pluripotent stem cells. Elongin BC is recruited to chromatin by the PRC2-associated factor EPOP (Elongin- and POlycomb-associated Protein, also termed C17orf96, esPRC2p48, E130012A19Rik), a protein expressed in the inner cell mass of the mouse blastocyst. Both EPOP and Elongin BC are required to maintain low levels of expression at PRC2 genomic targets. Our results indicate that keeping the balance between activating and repressive cues is a more general feature of chromatin in pluripotent stem cells than previously appreciated.

2016-11-21 | GSE79606 | GEO

Peptide-mediated inhibition of the transcriptional regulator Elongin BC induces apoptosis in cancer cells

Project description:Inhibiting protein-protein interactions via designed peptides is a suitable strategy to block the function of important proteins in cells. The Elongin BC heterodimer (ELOB/C) is involved in transcription elongation and protein turnover. It interacts with target proteins via a so-called BC-box to modulate their functions. ELOB and ELOC are commonly upregulated in cancer and are essential for cancer cell growth, making them attractive drug targets. However, currently, no strategy has been established to inhibit the function of ELOB/C in cells. Here, we show that peptides that mimic the high-affinity BC-box of EPOP can block the interaction of ELOB/C with its target proteins, both in vitro and in the cellular environment. Cancer cells treated with BC-box peptides, but not with the mutated control, show decreased cell viability, altered cell cycle and increased apoptosis, demonstrating a biological impact by inhibiting ELOB/C in vivo. Together our work suggests that targeting the BC-box binding pocket of ELOB/C is a feasible strategy to impair the function of the ELOB/C heterodimer and to inhibit cancer cell growth.

2023-06-27 | PXD038414 | Pride

Peptide-mediated inhibition of the transcriptional regulator Elongin BC induces apoptosis in cancer cells

Project description:Inhibition of protein-protein interactions (PPIs) via designed peptides is an effective strategy to perturb their biological functions. The Elongin BC heterodimer (ELOB/C) binds to a BC-box motif and is essential for cancer cell growth. Here, we report a peptide that mimics the high-affinity BC-box of the PRC2-associated protein EPOP. This peptide tightly binds to the ELOB/C dimer (kD = 0.46 ± 0.02 nM) and blocks the association of ELOB/C with its interaction partners, both in vitro and in the cellular environment. Cancer cells treated with our peptide inhibitor showed decreased cell viability, increased apoptosis, and perturbed gene expression. Therefore, our work proposes that blocking the BC-box-binding pocket of ELOB/C is a feasible strategy to impair its function and inhibit cancer cell growth. Our peptide inhibitor promises novel mechanistic insights into the biological function of the ELOB/C dimer and offers a starting point for therapeutics linked to ELOB/C dysfunction.

2023-06-24 | GSE213767 | GEO