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ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters

High expression of the transcription factor ZFX is correlated with proliferation, tumorigenesis, and patient survival in multiple types of human cancers. However, the mechanism by which ZFX influences transcriptional regulation has not been determined. We performed ChIP-seq in four cancer cell lines...

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Autores principales: Rhie, Suhn Kyong, Yao, Lijun, Luo, Zhifei, Witt, Heather, Schreiner, Shannon, Guo, Yu, Perez, Andrew A., Farnham, Peggy J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848610/
https://www.ncbi.nlm.nih.gov/pubmed/29429977
http://dx.doi.org/10.1101/gr.228809.117
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author Rhie, Suhn Kyong
Yao, Lijun
Luo, Zhifei
Witt, Heather
Schreiner, Shannon
Guo, Yu
Perez, Andrew A.
Farnham, Peggy J.
author_facet Rhie, Suhn Kyong
Yao, Lijun
Luo, Zhifei
Witt, Heather
Schreiner, Shannon
Guo, Yu
Perez, Andrew A.
Farnham, Peggy J.
author_sort Rhie, Suhn Kyong
collection PubMed
description High expression of the transcription factor ZFX is correlated with proliferation, tumorigenesis, and patient survival in multiple types of human cancers. However, the mechanism by which ZFX influences transcriptional regulation has not been determined. We performed ChIP-seq in four cancer cell lines (representing kidney, colon, prostate, and breast cancers) to identify ZFX binding sites throughout the human genome. We identified roughly 9000 ZFX binding sites and found that most of the sites are in CpG island promoters. Moreover, genes with promoters bound by ZFX are expressed at higher levels than genes with promoters not bound by ZFX. To determine if ZFX contributes to regulation of the promoters to which it is bound, we performed RNA-seq analysis after knockdown of ZFX by siRNA in prostate and breast cancer cells. Many genes with promoters bound by ZFX were down-regulated upon ZFX knockdown, supporting the hypothesis that ZFX acts as a transcriptional activator. Surprisingly, ZFX binds at +240 bp downstream from the TSS of the responsive promoters. Using Nucleosome Occupancy and Methylome Sequencing (NOMe-seq), we show that ZFX binds between the open chromatin region at the TSS and the first downstream nucleosome, suggesting that ZFX may play a critical role in promoter architecture. We have also shown that a closely related zinc finger protein ZNF711 has a similar binding pattern at CpG island promoters, but ZNF711 may play a subordinate role to ZFX. This functional characterization of ZFX provides important new insights into transcription, chromatin structure, and the regulation of the cancer transcriptome.
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spelling pubmed-58486102018-03-20 ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters Rhie, Suhn Kyong Yao, Lijun Luo, Zhifei Witt, Heather Schreiner, Shannon Guo, Yu Perez, Andrew A. Farnham, Peggy J. Genome Res Research High expression of the transcription factor ZFX is correlated with proliferation, tumorigenesis, and patient survival in multiple types of human cancers. However, the mechanism by which ZFX influences transcriptional regulation has not been determined. We performed ChIP-seq in four cancer cell lines (representing kidney, colon, prostate, and breast cancers) to identify ZFX binding sites throughout the human genome. We identified roughly 9000 ZFX binding sites and found that most of the sites are in CpG island promoters. Moreover, genes with promoters bound by ZFX are expressed at higher levels than genes with promoters not bound by ZFX. To determine if ZFX contributes to regulation of the promoters to which it is bound, we performed RNA-seq analysis after knockdown of ZFX by siRNA in prostate and breast cancer cells. Many genes with promoters bound by ZFX were down-regulated upon ZFX knockdown, supporting the hypothesis that ZFX acts as a transcriptional activator. Surprisingly, ZFX binds at +240 bp downstream from the TSS of the responsive promoters. Using Nucleosome Occupancy and Methylome Sequencing (NOMe-seq), we show that ZFX binds between the open chromatin region at the TSS and the first downstream nucleosome, suggesting that ZFX may play a critical role in promoter architecture. We have also shown that a closely related zinc finger protein ZNF711 has a similar binding pattern at CpG island promoters, but ZNF711 may play a subordinate role to ZFX. This functional characterization of ZFX provides important new insights into transcription, chromatin structure, and the regulation of the cancer transcriptome. Cold Spring Harbor Laboratory Press 2018-03 /pmc/articles/PMC5848610/ /pubmed/29429977 http://dx.doi.org/10.1101/gr.228809.117 Text en © 2018 Rhie et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research
Rhie, Suhn Kyong
Yao, Lijun
Luo, Zhifei
Witt, Heather
Schreiner, Shannon
Guo, Yu
Perez, Andrew A.
Farnham, Peggy J.
ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters
title ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters
title_full ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters
title_fullStr ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters
title_full_unstemmed ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters
title_short ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters
title_sort zfx acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of cpg island promoters
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848610/
https://www.ncbi.nlm.nih.gov/pubmed/29429977
http://dx.doi.org/10.1101/gr.228809.117
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