The synthetic histone-binding regulator protein PcTF activates interferon genes in breast cancer cells

Mounting evidence from genome-wide studies of cancer show that chromatin-mediated epigenetic silencing at large cohorts of genes is strongly linked to a poor prognosis. This mechanism is thought to prevent cell differentiation and enable evasion of the immune system. Drugging the cancer epigenome wi...

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Bibliographic Details
Published inbioRxiv
Main Authors Olney, Kimberly C, Nyer, David B, Vargas, Daniel A, Wilson Sayres, Melissa A, Haynes, Karmella
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 04.04.2018
Subjects
Breast cancer
Cell differentiation
Chromatin
Drug development
Drug resistance
Fusion protein
Gene expression
Gene silencing
Genomes
Histone H3
Immune system
Interferon
Lysine
Polycomb group proteins
Tumor cell lines
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Summary:Mounting evidence from genome-wide studies of cancer show that chromatin-mediated epigenetic silencing at large cohorts of genes is strongly linked to a poor prognosis. This mechanism is thought to prevent cell differentiation and enable evasion of the immune system. Drugging the cancer epigenome with small molecule inhibitors to release silenced genes from the repressed state has emerged as a powerful approach for cancer research and drug development. Targets of these inhibitors include chromatin-modifying enzymes that can acquire drug-resistant mutations. In order to directly target a generally conserved feature, elevated trimethyl-lysine 27 on histone H3 (H3K27me3), we developed the Polycomb-based Transcription Factor (PcTF), a fusion activator that targets methyl-histone marks via its N-terminal H3K27me3-binding motif, and co-regulates sets of silenced genes. Here, we report transcriptome profiling analyses of PcTF-treated breast cancer model cell lines. We identified a set of 19 PcTF-upregulated genes, or PUGs, that were consistent across three distinct breast cancer cell lines. These genes are associated with the interferon response pathway. Our results demonstrate for the first time a chromatin-mediated interferon-related transcriptional response driven by an engineered fusion protein that physically links repressive histone marks with active transcription.
DOI:10.1101/186056