Dual roles of c-Myc in the regulation of hTERT gene

Yuanjun Zhao; De Cheng; Shuwen Wang; Jiyue Zhu

doi:10.1093/nar/gku721

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Dual roles of c-Myc in the regulation of hTERT gene

Journal article

Open access

Peer reviewed

Dual roles of c-Myc in the regulation of hTERT gene

Yuanjun Zhao, De Cheng, Shuwen Wang and Jiyue Zhu

Nucleic acids research, Vol.42(16), pp.10385-10398

2014

DOI: https://doi.org/10.1093/nar/gku721

Handle:

https://hdl.handle.net/2376/105046

PMCID: PMC4176324

PMID: 25170084

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Abstract

Cell Line

Chromatin - metabolism

Promoter Regions, Genetic

Humans

Transcriptional Activation

Gene Expression Regulation

Proto-Oncogene Proteins c-myc - metabolism

E-Box Elements

DNA-Binding Proteins - metabolism

Transcription Factors - metabolism

Proto-Oncogene Proteins c-myc - physiology

Telomerase - biosynthesis

Telomerase - genetics

Chromosomes, Artificial, Bacterial

Transcription, Genetic

Histones - metabolism

RNA, Small Interfering - metabolism

Human telomerase gene hTERT is important for cancer and aging. hTERT promoter is regulated by multiple transcription factors (TFs) and its activity is dependent on the chromatin environment. However, it remains unsolved how the interplay between TFs and chromatin environment controls hTERT transcription. In this study, we employed the recombinase-mediated BAC targeting and BAC recombineering techniques to dissect the functions of two proximal E-box sites at -165 and +44 nt in regulating the hTERT promoter in the native genomic contexts. Our data showed that mutations of these sites abolished promoter binding by c-Myc/Max, USF1 and USF2, decreased hTERT promoter activity, and prevented its activation by overexpressed c-Myc. Upon inhibition of histone deacetylases, mutant and wildtype promoters were induced to the same level, indicating that the E-boxes functioned to de-repress the hTERT promoter and allowed its transcription in a repressive chromatin environment. Unexpectedly, knockdown of endogenous c-Myc/Max proteins activated hTERT promoter. This activation did not require the proximal E-boxes but was accompanied by increased promoter accessibility, as indicated by augmented active histone marks and binding of multiple TFs at the promoter. Our studies demonstrated that c-Myc/Max functioned in maintaining chromatin-dependent repression of the hTERT gene in addition to activating its promoter.

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Title: Dual roles of c-Myc in the regulation of hTERT gene
Creators: Yuanjun Zhao - Department of C & M Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
De Cheng - Department of C & M Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington, USA
Shuwen Wang - Department of C & M Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington, USA
Jiyue Zhu - Department of C & M Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington, USA jiyue.zhu@wsu.edu
Publication Details: Nucleic acids research, Vol.42(16), pp.10385-10398
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: England
Grant note: R01GM071725 / NIGMS NIH HHS
Identifiers: 99900546550101842
Language: English
Resource Type: Journal article